CN102482270B - Substituted piperidines - Google Patents

Substituted piperidines Download PDF

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CN102482270B
CN102482270B CN201080036220.XA CN201080036220A CN102482270B CN 102482270 B CN102482270 B CN 102482270B CN 201080036220 A CN201080036220 A CN 201080036220A CN 102482270 B CN102482270 B CN 102482270B
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compound
base
cis
phenyl
esipos
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CN102482270A (en
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D·海姆巴赫
S·勒里希
Y·坎乔格兰德
E·本德
K·齐默曼
A·布希米勒
C·格德斯
M·J·格诺特
K·M·格里克
M·耶斯克
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Bayer Pharma AG
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

The invention relates to novel substituted piperidines, to methods for the production thereof, to the use thereof for the treatment and/or prophylaxis of diseases and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular diseases and tumor diseases.

Description

The piperidines replaced
The present invention relates to the piperidines of new replacement, its preparation method, its be used for the treatment of and/or prophylactic application and its for the production for the treatment of and/or preventing disease, the particularly application of the medicine of cardiovascular disorder and tumor disease.
Thrombocyte (thrombocyte) is the important factor in physiological hemostasis method and in thromboembolic disorders.Particularly in Arterial system, during the title complex of thrombocyte between blood component and vessel wall interacts, there is center importance.By the formation of plateletrich thrombus, unwanted platelet activation may cause thromboembolic disorders and thrombosis complication, with life-threatening situation.
The most virtuous inducer of platelet activation of one is blood coagulation proteins enzyme zymoplasm, its vessel wall in damage is formed and it, except fibrinogen is formed, cause thrombocyte, endotheliocyte and mesenchymal cell activate (Vu TKH, Hung DT, Wheaton VI, Coughlin SR, Cell 1991,64,1057-1068).In thrombocyte in vitro and in animal model, the formation of Coagulative inhibitors agent anticoagulant and plateletrich thrombosis.On the person, artery thrombosis can successfully prevent with platelet function inhibitor and Coagulative inhibitors agent or treat (Bhatt DL, Topol EJ, Nat.Rev.Drug Discov.2003,2,15-28).Therefore, there is zymoplasm reduce thrombosis to the antagonist of Platelet and occur the high probability of clinical sequelae such as myocardial infarction and apoplexy.Other cytosis of zymoplasm, such as, to endotheliocyte and the smooth muscle cell of blood vessel, white cell and inoblast, may be responsible for inflammatory diseases and proliferative disease.
The cytosis of at least some zymoplasm passes through the regulation (Protease Activated Receptors, PARs) of a class G-protein-coupling, and its prototype is PAR-1 acceptor.PAR-1 is by the combination activation of zymoplasm with the Proteolytic cleavage of its extracellular N-end.Proteolysis exposes the new N-end having and cause the aminoacid sequence SFLLRN that molecule inner recipient activates and intracellular signal transmits as agonist.Derived from fastening-peptide of ligand sequence can be used as acceptor agonist and, cause activating and assembling to thrombocyte.Other proteolytic enzyme can activate PAR-1 equally, these proteases are as comprised plasmine, factor VIIa, factor Xa, trypsinase, the protein C (aPC) of activation, tryptase, cathepsin G, protease 3, granzyme A, Proteinase, bone marrow serine and matrix metallopeptidase 1 (MMP-1).
Contrary with suppressing the protease activity with the zymoplasm of direct Coagulative inhibitors agent, the suppression of raw for real estate platelet activation is not reduced the coagulability (anti-freezing) of blood by the blocking-up of PAR-1.
Antibody and other optionally PAR-1 antagonist are at low gathering (the Kahn ML suppressing external hematoblastic zymoplasm-induction under medium concentration of thrombin, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR, J.Clin.Invest.1999,103,879-887).To the further thrombin receptor of the possible importance of physiopathology tool of thrombotic method, PAR-4, to the identification of humans and animals thrombocyte.Have the animal of the PAR expression pattern being similar to people with it in experimental thrombosis, PAR-1 antagonist reduces formation (Derian CK, the Damiano BP of plateletrich thrombus, Addo MF, Darrow AL, D ' Andrea MR, Nedelman M, Zhang H-C, Maryanoff BE, Andrade-Gordon P, J.Pharmacol.Exp.Ther.2003,304,855-861).
In recent years, in order to their platelet function-restraining effect a large amount of material on inspection; But only have minority platelet function inhibitor to prove useful in practice.Therefore, exist for the platelet response specifically suppressing to increase and do not increase hemorrhage danger significantly, and thus reducing the needs of the medicine of the danger of thromboembolic complication.
The function influence of the zymoplasm regulated by the acceptor PAR-1 surgery in coronary artery bypass graft surgery (CABG) and other surgical operation and particularly comitative aspect outer circulation (such as pump oxygenator) and the progress of disease afterwards.At intra-operative, due to blood coagulation-suppression and/or thrombocyte-inhibitory substance in advance-or operation in drug treating may there is hemorrhage complication.For this reason, such as, several days must be interrupted before CABG by the drug treating of chlorine pyrrole lattice row.In addition, as mentioned, may produce disseminated intravascular coagulation or consumption coagulopathy (DIC) (such as circulation or the contact owing to expanding between blood and synthetic surface during transfusing blood in vitro), it may cause hemorrhage complication again.Subsequently, due to thrombosis, intimal fibrosis, arteriosclerosis, stenocardia, myocardial infarction, in heart failure, arrhythmia, often there is the restenosis (it even may produce obstruction) of the artery bypass of vein or transplanting in transient ischemic attack (TIA) (TIA) and/or apoplexy.
On the person, acceptor PAR-1 also comprises such as endotheliocyte with other cell, and smooth muscle cell and tumour cell represent.Malignancy disease (cancer) has high incidence and usually relevant with high mortality.Electric current therapy only obtains remission completely and general relevant with severe side effect in sub-fraction patient.Therefore more effective and safer treatment is highly needed.PAR-1 acceptor contributes to cancer and produces, growth, invades and transfer.In addition, the PAR-1 that endotheliocyte is expressed transmits the signal producing vasculogenesis (" blood vessel generation "), a kind of to making tumour than about 1mm 3the vital method of larger growth.The disease that other occurs also to contribute to blood vessel comprises such as hemopoietic Cancerous disease, macular degeneration (it causes blind), and diabetic retinopathy, inflammatory diseases, the generation of such as rheumatoid arthritis and colitis or deterioration.
Sepsis (or septicemia) is the common disease with high mortality.Pyemic initial symptom is generally uncertain (such as have a fever, the healthy state of whole body reduces); But, the whole body activation (" disseminated intravascular coagulation " or " consumption coagulopathy " (DIC)) with the blood coagulation system of microthrombusis in various organ and secondary hemorrhage complication may be there is afterwards.DIC can also independent of Sepsis such as at surgery or relevant with tumor disease to occur.
First pyemic treatment is the infectious reason of powerful removing, such as, by operation removing focus and antibiosis.Secondly, it is the medical science support of the strengthening of interim infected tract.Such as, in following publication (Dellinger etc., Crit Care Med.2004,32:858-873), described the treatment of this disease different steps.The treatment proved effective is not proved for DIC.
Therefore the object of this invention is to provide the new disease being used for the treatment of humans and animals, such as cardiovascular disorder and thromboembolic disorders, and the PAR-1 antagonist of tumor disease.
WO2006/012226, WO2006/020598, WO2007/038138, WO2007/130898, WO2007/101270 and US2006/0004049 describes and is used for the treatment of particularly diabetes as 11-beta hsd 1 inhibitors, the piperidines of the similar of thromboembolic disorders and apoplexy.
The invention provides following formula: compound
Wherein
R 1trifluoromethyl, 1,1-bis-fluoro ethyl, 2,2-bis-fluoro ethyl, 2,2,2-trifluoroethyl, difluoro-methoxy, trifluoromethoxy or ethyl,
R 22-hydroxyl second-1-base, 2-methoxyl group second-1-base, 2-oxyethyl group second-1-base, cyclopropyl or 1-methoxy basic ring third-1-base,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
If following this compound mentioned comprised by formula (I) is not also salt, the solvate of solvate and salt, then compound of the present invention is compound and their salt of formula (I), the solvate of solvate and salt, the compound of the following formula mentioned comprised by formula (I) and their salt and the solvate of salt and the following compound mentioned as embodiment comprised by formula (I) and their salt, the solvate of solvate and salt.
Depend on their structure, compound of the present invention may exist with stereomeric form (enantiomer, diastereomer).Therefore, the present invention includes enantiomer or diastereomer and their respective mixture.From the mixture of this enantiomer and/or diastereomer, the consistent component of stereoisomerism can be separated in known manner.
If compound of the present invention can exist with tautomeric form, then the present invention includes all tautomeric forms.
In the context of the present invention, preferably saltit is the physiologically acceptable salt of compound of the present invention.But, also comprise itself be not suitable for medicinal, but it can such as the separation of compound of the present invention or the salt of purification.
The physiologically acceptable salt of compound of the present invention comprises mineral acid, the acid salt of carboxylic acid and sulfonic acid, such as hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, fumaric acid, toxilic acid and benzoic salt.
The physiologically acceptable salt of compound of the present invention also comprises the salt of conventional alkali, such as with preferred as alkali salt (such as sodium salt and sylvite), alkaline earth salt (calcium salt and magnesium salts) and derived from ammonia or the ammonium salt of organic amine with 1 to 16 carbon atoms, such as, with preferred ethamine, diethylamine, triethylamine, ethyl diisopropylamine, Monoethanolamine MEA BASF, diethanolamine, trolamine, dicyclohexyl amine, dimethylaminoethanol, PROCAINE HCL, PHARMA GRADE, dibenzylamine, N-methylmorpholine, arginine, Methionin, quadrol, N-methyl piperidine and choline.
In the context of the present invention, solvatebe those forms according to compound of the present invention, it is with solid-state or liquid, forms title complex by coordinating with solvent molecule.Hydrate is the particular form of solvate, and wherein coordinating is carry out with water.
In addition, the present invention includes the prodrug of compound of the present invention.It itself may be biologic activity or inactive that term " prodrug " comprises, but transforms into the compound (such as by metabolism or hydrolysis) of compound of the present invention in their retention periods in health.
Can be R 3group formula in, the end points of the line marked by * does not represent carbon atom or CH 2group, but be and R 3a part for the key of the atom connected.
Preferred formula (I) compound, wherein
R 1trifluoromethyl, 1,1-bis-fluoro ethyl, 2,2-bis-fluoro ethyl, 2,2,2-trifluoroethyl, difluoro-methoxy, trifluoromethoxy or ethyl,
R 22-methoxyl group second-1-base, cyclopropyl or 1-methoxy basic ring third-1-base,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Also preferred formula (I) compound, wherein
R 1trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy or ethyl,
R 22-methoxyl group second-1-base, cyclopropyl or 1-methoxy basic ring third-1-base,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Also preferred formula (I) compound, wherein
R 1trifluoromethyl, 2,2,2-trifluoroethyl or trifluoromethoxy,
R 2cyclopropyl or 1-methoxy basic ring third-1-base,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Also preferred formula (I) compound, wherein
R 1trifluoromethyl, trifluoromethoxy or ethyl,
R 22-hydroxyl second-1-base, 2-methoxyl group second-1-base, 2-oxyethyl group second-1-base or cyclopropyl,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Also preferred formula (I) compound, wherein
R 1trifluoromethyl or ethyl,
R 22-hydroxyl second-1-base, 2-methoxyl group second-1-base or cyclopropyl,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Also preferred formula (I) compound, wherein
R 1trifluoromethyl or ethyl,
R 22-methoxyl group second-1-base,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Also preferred formula (I) compound, wherein
R 1trifluoromethyl or ethyl,
R 22-methoxyl group second-1-base,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Preferred formula (I) compound, wherein
R 1trifluoromethoxy,
R 22-methoxyl group second-1-base or cyclopropyl,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Preferred formula (I) compound, wherein
R 1trifluoromethoxy,
R 2cyclopropyl,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Preferred formula (I) compound, wherein
R 1trifluoromethoxy,
R 22-methoxyl group second-1-base or cyclopropyl,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt, their solvate and the solvate of their salt.
Also preferred formula (I) compound, wherein phenyl substituent and 1,2,4- diazole-5-base substituting group, it is connected to piperidine ring, at cis-position each other.
Also preferred formula (I) compound, the carbon atom that wherein phenyl substituent connects has S configuration and 1,2,4- the carbon atom that diazole-5-base substituting group connects has S configuration equally.
Also preferred formula (I) compound, wherein R 1it is trifluoromethyl.
Also preferred formula (I) compound, wherein R 1it is trifluoromethoxy.
Also preferred formula (I) compound, wherein R 1it is ethyl.
Also preferred formula (I) compound, wherein R 2it is 2-methoxyl group second-1-base.
Also preferred formula (I) compound, wherein R 2it is cyclopropyl.
Also preferred formula (I) compound, wherein R 2it is 1-methoxy basic ring third-1-base.
Also preferred formula (I) compound, wherein
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group.
Also preferred formula (I) compound, wherein
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group.
The group definition illustrated in each moiety combinations or preferred moiety combinations, does not rely on the combination of the group that each illustrates, is replaced by the group definition of other combinations on demand yet.
The combination of very particularly preferably above-mentioned two or more preferred scope.
Invention further provides preparation formula (I) compound, or their salt, the method for their solvate or the solvate of their salt, wherein
[A] following formula: compound
Wherein
R 1and R 2each is as above definition
React with following formula: compound
Wherein
R 3as above definition, and
X 1halogen, preferred bromine or fluorine, or hydroxyl or 4-nitrophenoxy,
Or
[B] formula (II) compound reacts with chloroformic acid 4-nitre phenyl ester and reacts with following formula: compound in subordinate phase in the first phase
R 3-H(IV)，
Wherein
R 3as above definition,
Or
[C] following formula: compound
Wherein
R 1and R 3each is as above definition
React with following formula: compound
Wherein
R 2as above definition,
Or
[D] following formula: compound
Wherein
R 1and R 2each is as above definition
React to produce following formula: compound with the m-chloroperoxybenzoic acid of 0.8 to 1.1 equivalents
Wherein
R 1and R 2each is as above definition
Or
The m-chloroperoxybenzoic acid of [E] formula (Ia) compound and 2.0 to 3.0 equivalents reacts to produce following formula: compound
Wherein
R 1and R 2each is as above definition.
Formula (Ia), (Ib) and (Ic) compound is the subset (Teilmenge) of formula (I) compound.
Work as X 1when being halogen, according to the reaction of method [A] usually in inert solvent, optionally depositing in case at alkali, preferably-30 DEG C to 50 DEG C temperature ranges, carry out under standard pressure.
Inert solvent is such as tetrahydrofuran (THF), methylene dichloride, pyridine, two alkane or dimethyl formamide, preferred methylene dichloride.
Alkali is, such as, and triethylamine, diisopropylethylamine or N-methylmorpholine, preferred triethylamine or diisopropylethylamine.
Work as X 1when being hydroxyl, according to the reaction of method [A] usually in inert solvent, depositing in case at dewatering agent, optionally deposit in case at alkali, preferably-30 DEG C to 50 DEG C temperature ranges, carry out under standard pressure.
Inert solvent is such as halohydrocarbon, such as methylene dichloride or trichloromethane, hydrocarbon polymer, such as benzene, Nitromethane 99Min., two alkane, dimethyl formamide or acetonitrile.The mixture of solvent can be used equally.Particularly preferably methylene dichloride or dimethyl formamide.
Dewatering agent suitable is in this article, such as, and carbodiimide, such as N, N '-diethyl-, N, N '-dipropyl-, N, N '-di-isopropyl-, N, N '-dicyclohexylcarbodiimide, N-(3-dimethylamino sec.-propyl)-N '-ethyl-carbodiimide hydrochloride (EDC), N-carbodicyclo hexylimide-N '-propyl group oxygen methyl polystyrene (PS-carbodiimide), or carbonyl compound, such as N,N'-carbonyldiimidazole, or 1,2- azoles compound, such as 2-ethyl-5-phenyl-1,2- azoles 3-vitriol or 2-tert-butyl-5-methyl different azoles perchlorate, or amido compounds, such as 2-oxyethyl group-1-ethoxy carbonyl-1,2-dihydroquinoline, or propane phosphoric acid acid anhydrides, or isobutyl chlorocarbonate, or two (2-oxo-3- oxazolidinyl) phosphoryl chloride or benzotriazole base oxygen base-three (dimethylamino) hexafluorophosphate, or O-(benzotriazole-1-base)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate (TPTU) or O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU), or I-hydroxybenzotriazole (HOBt), or benzotriazole-1-base oxygen base three (dimethylamino) hexafluorophosphate (BOP), or N-hydroxy-succinamide, or the mixture of these and alkali.
Alkali is, such as, and alkaline carbonate, such as sodium carbonate or salt of wormwood, or sodium bicarbonate or saleratus, or organic bases, such as trialkylamine, such as triethylamine, N-methylmorpholine, N-methyl piperidine, 4-dimethylaminopyridine or diisopropylethylamine.
Preferably, condensation is deposited at HOBt and is carried out with HATU or with EDC in case.
Work as X 1when being 4-nitrophenoxy, according to the reaction of method [A] usually in inert solvent, optionally depositing in case at alkali, optionally in microwave, preferably 50 DEG C to 200 DEG C temperature ranges, carry out under standard pressure to 5 bar.
Inert solvent is, such as N-Methyl pyrrolidone, two alkane or dimethyl formamide, preferred N-Methyl pyrrolidone.
Alkali is, such as triethylamine, diisopropylethylamine or N-methylmorpholine, preferred triethylamine or diisopropylethylamine.
Formula (III) compound is known or can be synthesized by suitable initial compounds by known method.
Usual in inert solvent according to the first stage reaction of method [B], deposit in case at alkali, preferably 0 DEG C to 50 DEG C temperature range, carry out under standard pressure.
Inert solvent is, such as halohydrocarbon, such as methylene dichloride, trichloromethane, tetrachloromethane or 1,2-ethylene dichloride, preferred methylene dichloride.
Alkali is, such as organic bases, such as trialkylamine, such as triethylamine, N-methylmorpholine, N-methyl piperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferred triethylamine.
According to the reaction of the subordinate phase of method [B] usually in inert solvent, deposit in case at alkali, optionally in microwave, preferably 50 DEG C to 200 DEG C temperature ranges, carry out under standard pressure to 5 bar.
Inert solvent is, such as, and dimethyl sulfoxide (DMSO), dimethyl formamide or N-Methyl pyrrolidone, preferred dimethyl formamide.
Alkali is, such as, and alkaline carbonate, such as sodium carbonate or salt of wormwood, preferred salt of wormwood.
Formula (IV) compound is known or can be synthesized by suitable precursor compound by known method.
According to the reaction of method [C] usually in inert solvent, deposit in case at dewatering agent, optionally deposit in case at alkali, preferably by room temperature to the reflow temperature range of solvent, carry out under standard pressure.
Inert solvent is, such as, and halohydrocarbon, such as methylene dichloride, trichloromethane or 1,2-ethylene dichloride, ether, such as two alkane, tetrahydrofuran (THF) or 1,2-glycol dimethyl ether, or other solvent, such as acetone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, 2-butanone or acetonitrile.Also may use the mixture of solvent.Preferred dimethyl formamide or two the mixture of alkane and dimethyl formamide.
Dewatering agent suitable is in this article, such as, and carbodiimide, such as N, N '-diethyl-, N, N '-dipropyl-, N, N '-di-isopropyl-, N, N '-dicyclohexylcarbodiimide, N-(3-dimethylamino sec.-propyl)-N '-ethyl-carbodiimide hydrochloride (EDC), N-carbodicyclo hexylimide-N '-propyl group oxygen methyl polystyrene (PS-carbodiimide), or carbonyl compound, such as N,N'-carbonyldiimidazole, or 1,2- azoles (oxazolium) compound, such as 2-ethyl-5-phenyl-1,2- azoles 3-vitriol or 2-tert-butyl-5-methyl different azoles perchlorate, or amido compounds, such as 2-oxyethyl group-1-ethoxy carbonyl-1,2-dihydroquinoline, or propane phosphoric acid acid anhydrides, or isobutyl chlorocarbonate, or two (2-oxo-3- oxazolidinyl) phosphoryl chloride or benzotriazole base oxygen base-three (dimethylamino) hexafluorophosphate, or O-(benzotriazole-1-base)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate (TPTU) or O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU), or I-hydroxybenzotriazole (HOBt), or benzotriazole-1-base oxygen base three (dimethylamino) hexafluorophosphate (BOP), or benzotriazole-1-base oxygen base three (tetramethyleneimine also) hexafluorophosphate (PYBOP), or N-hydroxy-succinamide, or the mixture of these and alkali.
Alkali is, such as, and alkaline carbonate, such as sodium carbonate or salt of wormwood, or sodium bicarbonate or saleratus, or organic bases, such as trialkylamine, such as triethylamine, N-methylmorpholine, N-methyl piperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferred diisopropylethylamine.
Preferably, condensation is deposited in case with HATU or only carry out with N,N'-carbonyldiimidazole at diisopropylethylamine.
Formula (VI) compound is known or can be synthesized by suitable initial compounds by known method.
According to the reaction of method [D] usually in inert solvent, preferably in room temperature to the reflow temperature range of solvent, carry out under standard pressure.
M-chloroperoxybenzoic acid preferably uses with the amount of 0.9 to 1.0 equivalents.
Inert solvent is such as halohydrocarbon, such as methylene dichloride, trichloromethane or 1,2-ethylene dichloride.Preferred methylene dichloride.
According to the reaction of method [E] usually in inert solvent, preferably in room temperature to the reflow temperature range of solvent, carry out under standard pressure.
M-chloroperoxybenzoic acid, preferably with the amount of 2.3 to 2.6 equivalents, is more preferably and uses with the amount of 2.5 equivalents.
Inert solvent is such as halohydrocarbon, such as methylene dichloride, trichloromethane or 1,2-ethylene dichloride.Preferred methylene dichloride.
Formula (II) compound is known or can passes through following formula: compound
Wherein
R 1as above definition
Prepare with formula (VI) compound with in subordinate phase with acid-respons in the first phase.
First stage reaction is carried out as described ground for method [C].
Subordinate phase reaction usually in inert solvent, preferably in room temperature to 60 DEG C of temperature ranges, carry out under standard pressure.
Inert solvent is, such as halohydrocarbon, such as methylene dichloride, trichloromethane, tetrachloromethane or 1,2-ethylene dichloride, or ether, such as tetrahydrofuran (THF) or two alkane, preferred methylene dichloride.
Alkali is, such as trifluoroacetic acid or two hydrogenchloride in alkane, preferred trifluoroacetic acid.
Formula (VII) compound is known or can passes through following formula: compound
Wherein
R 1as above definition and
R 4methyl or ethyl,
In the first phase with dicarboxylic acid di-tert-butyl and
Prepare with alkali reaction in subordinate phase.
First stage, reaction was usually in inert solvent, deposited in case at alkali, preferably in room temperature to 50 DEG C of temperature ranges, carry out under standard pressure.
Inert solvent is, such as halohydrocarbon, such as methylene dichloride, trichloromethane, tetrachloromethane or 1,2-ethylene dichloride, preferred methylene dichloride.
Alkali is, such as, and triethylamine, diisopropylethylamine or N-methylmorpholine, preferred triethylamine or diisopropylethylamine.
Subordinate phase reaction, usually in inert solvent, is deposited in case at alkali, preferably in room temperature to the reflow temperature range of solvent, carry out under standard pressure.
Inert solvent is, such as halohydrocarbon, such as methylene dichloride, trichloromethane, tetrachloromethane or 1,2-ethylene dichloride, alcohol, such as methyl alcohol or ethanol, ether, such as ether, methyl tert-butyl ether, I, 2-glycol dimethyl ether, two alkane or tetrahydrofuran (THF), or other solvent, such as dimethyl formamide, N,N-DIMETHYLACETAMIDE, acetonitrile or pyridine, or the mixture of solvent, or the mixture of solvent and water, particular methanol or methyl alcohol and monovalent water, or the mixture of tetrahydrofuran (THF) and water.
Alkali is such as alkali metal hydroxide, such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkaline carbonate, such as cesium carbonate, sodium carbonate or salt of wormwood, or alkoxide, such as uncle-butanols potassium or uncle-sodium butylate, preferred lithium hydroxide or potassium tert.-butoxide.
Formula (VIII) compound is known or can be prepared by hydrogenation following formula: compound
Wherein
R 1and R 4each is as above definition.
Hydrogenation is usually in inert solvent, optional interpolation acid such as mineral acid and carboxylic acid, preferred acetic acid, preferably in the temperature range of room temperature to the reflux temperature of solvent and in the pressure range that standard pressure to 100 clings to, preferably carries out with reductive agent under standard pressure or 50-80 bar.
Preferred reductive agent is hydrogen and palladium on activated carbon, with rhodium on activated carbon, with ruthenium on activated carbon or its mixed catalyst, or hydrogen and the palladium on alumina or with the rhodium on alumina, or hydrogen and palladium on the activated carbon and platinum oxide (IV), preferred hydrogen and palladium on activated carbon or with rhodium on activated carbon or hydrogen and palladium on the activated carbon and platinum oxide (IV).Also hydrogen and independent platinum oxide (IV) hydrogenation can only be used under stress.
Inert solvent is, such as alcohol, such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, n-butanols or uncle-butanols, or spirit acid or methyl alcohol are with adding concentrated hydrochloric acid, and particular methanol or ethanol or spirit acid or methyl alcohol are with adding concentrated hydrochloric acid.
Formula (IX) compound is known or can passes through following formula: compound
Wherein
R 4as above definition
React with following formula: compound and prepare
Wherein
R 1as above definition.
This reaction, usually in inert solvent, in the presence of a catalyst, is optionally deposited in case at other reagent, preferably in room temperature to the reflow temperature range of solvent, carry out under standard pressure.
Inert solvent is, such as ether, such as two alkane, tetrahydrofuran (THF) or 1,2-glycol dimethyl ether, hydrocarbon polymer, such as benzene, dimethylbenzene or toluene, or other solvent, such as oil of mirbane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) or N-Methyl pyrrolidone; Optionally in these solvents, add little water.Preferred toluene and water or 1,2-glycol dimethyl ether, the mixture of dimethyl formamide and water.
Catalyzer is, such as, for the palladium catalyst that Suzuki reaction conditions is common, preferred catalyst, two (triphenylphosphine) palladium of such as dichloro, tetra-triphenylphosphine palladium (0), palladium (II) or two (Diphenyl phosphino ferrocene) Palladous chloride (II).
Other reagent is, such as, and potassium acetate, cesium carbonate, salt of wormwood or sodium carbonate, hydrated barta, potassium tert.-butoxide, cesium fluoride, Potassium monofluoride or potassiumphosphate, or its mixture, preferred fluorinated potassium or sodium carbonate, or the mixture of Potassium monofluoride and salt of wormwood.
Formula (X), (XI) and (XIII) compound is known or can be synthesized by suitable initial compounds by known method.
Formula (V) compound is known or can passes through following formula: compound
Wherein
R 1and R 3each as above definition and
R 4methyl or ethyl,
Prepare with alkali reaction.
This reaction, usually in inert solvent, is deposited in case at alkali, preferably from room temperature to the reflow temperature range of solvent, carries out under standard pressure.
Inert solvent is, such as halohydrocarbon, such as methylene dichloride, trichloromethane, tetrachloromethane or 1,2-ethylene dichloride, alcohol, such as methyl alcohol or ethanol, ether, such as ether, methyl tert-butyl ether, 1,2-glycol dimethyl ether, two alkane or tetrahydrofuran (THF), or other solvent, such as dimethyl formamide, N,N-DIMETHYLACETAMIDE, acetonitrile or pyridine, or the mixture of solvent, or the mixture of solvent and water, particular methanol or methyl alcohol and monovalent water, or the mixture of tetrahydrofuran (THF) and water.
Alkali is, such as alkali metal hydroxide, such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkaline carbonate, such as cesium carbonate, sodium carbonate or salt of wormwood, or alkoxide, such as uncle-butanols potassium or uncle-sodium butylate, preferred lithium hydroxide or potassium tert.-butoxide.
Formula (XII) compound is known or through type (VIII) compound and formula (III) compound can reacts and prepare.
This reaction is carried out as method [A] describes ground.
In other method, formula (XII) compound can through type (VIII)) compound reacts with fluorine formic acid 4-nitro phenyl ester in the first phase and reacts with formula (IV) compound in subordinate phase and prepare.
This reaction is carried out as method [B] describes ground.
The preparation of formula (I) compound can be illustrated by following synthesis scheme.
Diagram:
Compound display of the present invention is a kind of unpredictalbe, useful pharmacology and pharmacokinetics action spectrum.They are optionally antagonists of PAR-1 acceptor, particularly as anticoagulant, as the inhibitor of activated endothelial cell, and the inhibitor as smooth muscle cell proliferation and the inhibitor as tumor growth.For the some diseases mentioned, such as, with the cardiovascular disorder of high thromboembolism risk, the simple operations of the antergic permanent protection of PAR-1 concomitant drugs treatment is simultaneously most important.The independent oral rear effect lastingly of PAR-1 antagonist display of the present invention, i.e. effect lasts at least 16 hours.
Therefore, they are suitable for use as the medicine of the disease being used for the treatment of and/or preventing humans and animals.
Invention further provides compound of the present invention to be used for the treatment of and/or preventing disease, the application of preferred thromboembolic disorders and/or thromboembolic complication.
" thromboembolic disorders " comprises disease especially in the sense of the present invention, such as ST section Elevation Myocardial Infarction (STEMI) and non-ST section Elevation Myocardial Infarction (non-STEMI), stable angina pectoris, unstable angina pectoris, Percutantnoeus coronary intervention, such as angioplasty, inaccessible again and restenosis after stenter to implant or aortocoronary by-pass, peripheral arterial occlusion disease, pulmonary infarction, venous thrombosis and renal venous thrombosis, transient ischemic attack (TIA) and thrombosis and thromboembolytic stroke.
This material be therefore also suitable for suffer from acute, intermittence or the ARR patient of persistence orifice of the stomach, such as atrial fibrillation, with carry out those of cardioversion, and suffer from valvular heart disease or suffer from Ink vessel transfusing object, such as artificial heart valve, conduit, the cardiogenic thromboembolism of prevention and therapy in the patient of intra-aortic balloon counterpulsation and pacemaker probe, such as cerebral ischaemia, apoplexy and general thromboembolism and local asphyxia.
Thromboembolic complication also with microangiopathic hemolytic anemia, extracorporeal circulation, such as hemodialysis, blood filtering, ventricle assist devices and artificial heart, relevant with heart valve prosthesis.
In addition, compound of the present invention, also for affecting wound healing, prevents and/or treats disease and the inflammatory diseases of atherosclerotic's blood vessel for this, the rheumatosis disease of such as motor system, coronary heart disease, in heart failure, hypertension, inflammatory diseases, such as asthma, COPD, pulmonary inflammatory disease, glomerulonephritis and inflammatory bowel disease, and in addition for preventing and/or treating alzheimer's disease, autoimmune disease, Crohn's disease and ulcerative colitis.
In addition, compound of the present invention can be used for Tumor suppression growth and transfer, microangiopathy, with age-relevant macular degeneration, diabetic retinopathy, diabetogenous ephrosis and other microvascular disease, with prevention and therapy thromboembolic complication, such as venous thromboembolism, for tumour patient, particularly carries out those of large surgical operation or chemotherapy or radiotherapy.
Compound of the present invention is suitable for treating cancer in addition.Cancer comprises: malignant tumour (comprises mammary cancer, hepatocellular carcinoma, lung cancer, colorectal carcinoma, the cancer of colon and melanoma), lymphoma (such as non-Hodgkin lymphoma and mycosis fungoides), leukemia, sarcoma, mesothelioma, the cancer of the brain (such as neurospongioma), germinoma (such as carcinoma of testis and ovarian cancer), choriocarcinoma, kidney, pancreas cancer, thyroid carcinoma, head and neck cancer, carcinoma of endometrium, cervical cancer, bladder cancer, cancer of the stomach and multiple myeloma.
In addition, the PAR-1 that endotheliocyte is expressed regulates the signal causing angiogenic growth (" vasculogenesis "), and the method is important for enabling tumor growth exceed about 1mM.The induction of vasculogenesis also with other disease, comprise the disease (such as rheumatoid arthritis) of rheumatosis type, lung disease (such as pulmonary fibrosis, pulmonary hypertension, particularly pulmonary hypertension, is characterised in that the disease of lung obturation), arteriosclerosis, plaque rupture, diabetic retinopathy is relevant with wet macular degeneration.
In addition, compound of the present invention is suitable for treating septicemia.Septicemia (or septicemia) is the common disease with high mortality.The initial symptom of septicemia is generally nonspecific (such as have a fever, whole body health situation reduces), but may there is the whole body activation (" disseminated inravascular coagulation " or " consumption coagulopathy " of blood coagulation system afterwards; Hereinafter referred to as " DIC "), with formation and the secondary bleeding complications of microthrombus disease in various organ.In addition, endothelial injury may be had to increase and liquid and the albumen intravasation external space with the perviousness of conduit.When disease progression, organ dysfunction or organ failure (such as renal failure, liver failure, respiratory insufficiency, the defect of central nervous system and the heart/circulatory failure) and even multiple organ failure may be there is.In principle, this may affect any organ; The organ dysfunction that great majority often run into and organ failure are lungs, kidney, cardiovascular systems, blood coagulation system, central nervous system, the dysfunction of incretory gland and liver and exhaustion.Septicemia may be relevant with " acute dyspnea syndrome " (hereinafter referred to as ARDS).ARDS independently can also occur with septicemia." septic shock " relates to generation ypotension, and it must be treated, and promotes further organ damage and relevant with the deterioration of prejudging of symptom.
Pathogenic agent can be bacterium (Gram-negative and Gram-positive), fungi, virus and/or eukaryote.To enter or the position of primary infection may be such as pneumonia, the infection of urinary tract or peritonitis.Infect possibility, but may not, relevant with microbemia.
Septicemia is defined as to exist and infects and " general inflammatory response syndrome " (hereinafter referred to as " SIRS ").SIRS occurs between period of infection, but also in other situation, such as, damages, burn, shock, operation, local asphyxia, pancreatitis, recovery or tumor stage between.ACCP/SCCM Consensus Conference Committee of 1992 (Crit.Care Med.1992,20, definition 864-874) describes symptom that diagnosis " SIRS " needs and location parameter (comprises Temperature changing, the heart rate increased, the change of expiratory dyspnea and blood picture).The latter (2001) SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference adheres to this standard substantially, but fine tuning details (Levy etc., Crit.Care Med.2003,31,1250-1256).
DIC and SIRS may during septicemia, and as operation, tumor disease, the result of burn or other damage occurs.In DIC situation, there is the endothelial cell surface of blood coagulation system in damage, the surface of the extravascular tissue of foreign matter or damage activates in a large number.Therefore, to there is in the little conduit of various organ blood coagulation with hypoxemia and organ dysfunction subsequently.Side effect is thrombin (such as factor X, thrombogen, Fibrinogen) and platelet consumption, and it reduces the coagulability of blood and may may cause a large amount of bleeding.
In addition, compound of the present invention can also be used for preventing external blood coagulation, such as preserving blood and blood plasma product, for clean/pre-treatment conduit and other medical facilities and instrument, comprise extracorporeal circulation, in coated body or the surface of the medical facilities of external use and the synthesis of instrument or for comprising hematoblastic biological material.
The compound of the present invention that invention further provides such as, for applying medical instruments and implant, conduit, artificial limb, the application of support or artificial heart valve.Compound of the present invention can firmly be attached to surface or, for local action, through discharging into direct environment by carrier coating after a while.
Invention further provides compound of the present invention for treating and/or preventing disease, particularly the application of this above-mentioned disease.
Invention further provides compound of the present invention generation is used for the treatment of and/or preventing disease, particularly the application of the medicine of above-mentioned disease.
Invention further provides the one compounds for treating of the present invention and/or preventing disease, the particularly method of above-mentioned disease that use treatment significant quantity.
Invention further provides and comprise compound of the present invention and one or more further activeconstituentss, especially for the medicine treating and/or preventing above-mentioned disease.The activeconstituents being suitable for combining comprises, such as and preferably:
Calcium channel blocker, such as amlodipine besylate (such as ), felodipine, Odizem, verapamil, NIFEDIPINE, nicardipine, nisoldipine and Bepridil;
Lomerizine;
Statin, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, Pravastatin, Rosuvastatin and Simvastatin;
Cholesterol absorption inhibitor, such as, replace rice and AZD4121 according to pool;
Cholesteryl ester transfer protein (" CETP ") inhibitor, such as torcetrapib;
Low molecular weight heparin, such as dalteparin sodium, Ardeparin Sodium, certoparin, enoxaparin, Parnaparin Sodium, TINZ, reviparin and nadroparin calcium;
Further antithrombotics, such as warfarin, marcumar, fondaparin;
Anti-arrhythmic, such as P162a, ibutilide, metoprolol, metoprolol tartrate, Proprasylyte, atenolol USP 23, rauwolfine, disopyramide, Prajmaline, pronestyl, Quinidine, Tocosamine, Lilly 99170, lignocaine, mexiletine, tocainide, encainide, Tamboar, Ractopamine, Moracizine, Propafenone, acebutolol, pindolol, atlansil, Bretylium Tosylate, Meregon, sotalol, adenosine, coromegine and digoxin;
Alpha-adrenergic agonist, such as doxazosin mesylate, terazosin and Prazosin;
Beta-adrenergic blocking agent, such as carvedilol, Proprasylyte, timolol, nadolol, atenolol USP 23, metoprolol, bisoprolol, nebivolol, betaxolol, acebutolol and bisoprolol;
Aldosterone antagonist, such as eplerenone and Spironolactone;
Angiotensin-converting enzyme inhibitor (" ACE inhibitor "), such as moexipril, quinapril hydrochloride, Ramipril, lisinopril, benazepril hydrochloride, enalapril, captopril, spirapril, perindopril, fosinopril and Trolapril;
Angiotensin-ii receptor retarding agent (" ARBs "), such as olmesartan medoxomill, Candesartan, valsartan, telmisartan, irbesartan, losartan and Eprosartan;
Endothelin antagonists, such as tezosentan, bosentan and Si Tashengtan-sodium;
The inhibitor of neutral endopeptidase, such as candoxatril and ecadotril;
Phosphodiesterase inhibitor, such as milrinone, theophylline, vinpocetin, EHNA (red-9-(2-hydroxyl-3-nonyl) VITAMIN B4), Virga, Vardenafil and Tadalafil (Cialis);
Fibrinolytic agent, such as reteplase, alteplase and tenecteplase;
GP IIb/IIIa antagonist, such as eptifibatide, ReoPro and Tirofiban;
Direct coagulation inhibitor, such as AZD0837, argatroban, Bivalirudin and dabigatran;
Indirect coagulation inhibitor, such as ground difficult to understand handkerchief west;
Direct and indirect factor Xa inhibitor, such as fondaparin-sodium, Eliquis, razaxaban, razaxaban (BAY 59-7939), KFA-1982, DX-9065a, AVE3247, otamixaban (XRP0673), AVE6324, SAR377142, Chinese mugwort bends heparin, SSR126517, DB-772d, DT-831j, YM-150,813893, LY517717 and DU-1766;
Direct and indirect factor Xa/IIa inhibitor, such as enoxaparin-sodium, AVE5026, SSR128428, SSR128429 and BIBT-986 (Ta Nuoji group);
Lipoprotein-associated phospholipase A2 (" LpPLA2 ") conditioning agent;
Diuretic(s), such as chlorthalidone, Uregit, furosemide, guanamprazine, chlorothiazide, Zestoretic, Methyclothiazide and benzthiazide;
Nitric ether, such as 5-ISMN;
Thromboxane antagonists, such as seratrodast, Pirodomast and Ramatroban;
Anticoagulant, such as chlorine pyrrole lattice row, ticlopidine, Cilostazole, Asprin, ReoPro, limaprost, Integrilin and CT-50547;
Cyclooxygenase inhibitors, such as meloxicam, rofecoxib and celecoxib;
B-type natriuretic peptide, such as Nesiritide, ularitide;
NV1FGF conditioning agent, such as XRP0038;
HT1B/5-HT2A antagonist, such as SL65.0472;
Guanylate cyclase activators, such as A Taxi croak (HMR1766), HMR1069, riociguat and cinaciguat;
E-NOS transcriptional enhancer factor, such as AVE9488 and AVE3085;
Antiatherogenic material, such as AGI-1067;
CPU inhibitor, such as AZD9684;
Renin inhibitor, such as aliskiren (aliskirin) and VNP489;
The inhibitor of the platelet aggregation of adenosine diphosphate (ADP)-induction, such as chlorine pyrrole lattice row, ticlopidine, prasugrel, AZD6140, ADZ6140 and Yi Nuo Gray;
NHE-1 inhibitor, such as AVE4454 and AVE4890.
Antibiotic therapy: when planned treatment (Microorganism Evaluation make before) or when specifically treating, various microbiotic or antimycotic drug regimen are suitable; Liquid undergoing treatment, such as crystal or colloidal liquid; Vasopressor, such as norepinephrine, Dopamine HCL or beta-hypophamine; Muscular strength is treated, such as dobutamine; Corticosteroid, such as hydrocortisone, or fluohydrocortisone; Recombinant human activated protein C, Xigris; Blood products, such as red blood corpuscle enriched material, platelet concentrate, erythropoietin or fresh frozen plasma; Assisted ventilation, such as permitted deformation in the acute lung injury (ALI) or acute dyspnea syndrome (ARDS) of septicemia-induction, low tidal volumes; Calm: such as to stabilize, L0, midazolam or propofol.Opioid: such as fentanyl, hydromorphone, morphine, dolantin or remifentanil.NSAIDs: such as ketorolac, Ibuprofen BP/EP or acetaminophen.Neuromuscular blockade: such as pancuronium bromide; Glucose controls, such as Regular Insulin, glucose; Kidney replacement therapy, such as continuous print Veno-Venous Hemofiltration filters or intermittent hemodialysis.For kidney protection low-dosage Dopamine HCL; Antithrombotics, such as, for thrombosis prevention or such as, for kidney replacement therapy, unfractionated heparin, low molecular weight heparin, heparitin, r-hirudin, Bivalirudin or argatroban; Bicarbonate therapy; Stress ulcer is prevented, such as H2 acceptor inhibitor, antacid.
Medicine for proliferative disorders: uridylic, mustargen, endoxan, ifosfamide, melphalan, Chlorambucil, pipobroman, triethylene melamine, triethylene thiophosphoric acid amine, Myelosan, carmustine, lomustine, U-9889, dacarbazine, methotrexate, 5 FU 5 fluorouracil, floxuridine, cytosine arabinoside, Ismipur, 6-thioguanine, fludarabine phosphate, pentostatin, vincaleucoblastine, vincristine(VCR), desacetyl vinblastine amide, bleomycin, actinomycin, daunorubicin, adriamycin, epirubicin, idarubicin, taxol, mithramycin, deoxycoformycin, ametycin, L-asparaginase, Interferon, rabbit, Etoposide, teniposide, 17 α-lynoral, stilboestrol, testosterone, prednisone, fluorohydrocarbon methyltestosterone, Masterone, testolactone, megestrol, tamoxifen, methyl meticortelone, methyltestosterone, Prednisolone Acetate, fluorine hydroxyl prednisolone, chlorotrianisene (TACE), hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, Leuprolide, Drogenil, toremifene, goserelin, Platinol, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, L-tetramisole, nvelbine, Anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethyl melamine, oxaliplatin iressa (Gefitinib, Zdl839), (capecitabine), (Tarceva), azacitidine (U-18496, 5-AzaC), Temozolomide gemcitabine (such as (gemcitabine hydrochloride)), or above two or more combination.
Invention further provides for the external method of solidifying of anti-Hemostatic Oral Liquid, particularly at storehouse blood or comprise in hematoblastic biological material, it is characterized in that the compound of the present invention adding anti-freezing amount.
Compound of the present invention can whole body and/or local work.For this purpose, they can with suitable process, such as, by mouth, and parenteral, lung, nose, sublingual, tongue, cheek, rectum, epidermis, through skin, conjunctiva, ear path or take as implant or support.
Can take with the form being suitable for these route of administration according to compound of the present invention.
Be according to prior art effect for oral suitable form of taking and promptly and/or in an improved way transmit according to compound of the present invention, and comprise with those of compound of the present invention of form that is crystallization and/or unbodied and/or that dissolve, such as tablet (uncoated or such as there is the undissolvable or enteric coating of delayed dissolved and Co ntrolled release compound of the present invention or the sugar coated tablet of coating), the tablet of promptly disintegration in mouth, or film/film, film/lyophilized products, capsule (such as hard or soft gelatine capsule), coated tablet, particle, ball, powder, emulsion, suspension, aerosol or solution.
Parenteral admistration can be avoided absorption step (such as intravenously, intra-arterial, intracardiac, in backbone or in waist) or carry out with comprising absorption (such as subcutaneous, intracutaneous, in skin or abdomen) simultaneously.The form of taking being suitable for parenteral admistration comprises the preparation for injecting and preserved material in the form of a solution, suspension, emulsion, lyophilized products or aseptic powder.
Preferred oral.
Be suitable for another route of administration, such as, for sucking the medicament forms of (especially powder inhalator, spraying gun), nasal drop, solution, sprays; For tongue, the tablet that sublingual or cheek is taken, film/film or capsule, suppository, for the preparation of ear and eye, vaginal capsule, aqeous suspension (washing lotion, oscillation mixture), oil loving suspension, ointment, emulsifiable paste, percutaneous absorption type (such as patch), emulsion, paste, foam, face powder, implant or support.
According to compound of the present invention can change into mention take form.This can in a way known by carrying out with inertia, nontoxic, that pharmacology is suitable mixed with excipients.These vehicle comprise carrier (such as Microcrystalline Cellulose, lactose, mannitol), solvent (such as liquid macrogol), emulsifying agent and dispersion agent or wetting agent (such as sodium lauryl sulphate, polyoxyethylene sorbitan oleic acid ester), tackiness agent (such as polyvinylpyrrolidone), synthesis with natural polymkeric substance (such as albumin), stablizer (such as antioxidant, such as xitix), tinting material (such as mineral dye, such as ferriferous oxide) and shelter spices and/or odorant.
Invention further provides and comprise at least one compound of the present invention, preferably together with one or more inertia, nontoxic, the medicine of the acceptable vehicle of medicine, and they are for the application of above-mentioned object.
In parenteral admistration method situation, usually have been found that every 24 hours about doses of 5 to 250mg are favourable to obtaining effective result.In oral situation, dosage arrives 100mg in approximately every 24 hours 5.
But the amount as described in suitable departing from, particularly according to body weight, route of administration, individual for activeconstituents reaction, the character of preparation and take time of generation or interval may be necessary.
Below test and embodiment in per-cent be weight percent, except as otherwise noted; Part is weight part.For the solvent ratio of liquid/liquid solution, thinning ratio and concentration data are at each occurrence based on volume." w/v " is meant to " weight/volume ".Such as " 10%w/v " is meant to: 100ml solution or suspension comprise 10g material.
A) embodiment
abbreviation:
Approx. about
CDI N,N'-carbonyldiimidazole
D days, bimodal (in NMR)
TLC thin-layer chromatography
DCI direct chemical ionization (in MS)
Dd double doublet (in NMR)
DMAP 4-dimethylaminopyridine
DMF DMF
DMSO dimethyl sulfoxide (DMSO)
DPPA phosphazide diphenyl phthalate (Diphenylphosphorazidat)
DSC bis-succinimidyl carbonate
Eq. equivalent
ESI electrospray ionization (in MS)
H hour
HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate
HPLC high efficient, high pressure liquid chromatography
LC-MS liquid chromatograph mass spectrography
LDA lithium diisopropyl amido
M multiplet (in NMR)
Min minute
MS mass spectrum
NMR nuclear magnetic resonance spectrum
PYBOP benzotriazole-1-base oxygen base three (pyrrolidyl) hexafluorophosphate
Q quartet (in NMR)
RP anti-phase (in HPLC)
RT room temperature
Rt retention time (in HPLC)
S unimodal (in NMR)
T triplet (in NMR)
THF tetrahydrofuran (THF).
hPLC method:
method 1A:instrument: there is the HP 1100 that DAD detects; Post: Kromasil 100RP-18,60mm × 2.1mm, 3.5 μm; Elutriant A:5ml perchloric acid (70%)/L water, elutriant B: acetonitrile; Gradient: 0min 2%B → 0.5min 2%B → 4.5min 90%B → 6.5min 90%B → 6.7min 2%B → 7.5min 2%B; Flow velocity: 0.75ml/min; Column temperature: 30 DEG C; UV detects: 210nm.
lC-MS method:
method 1B:mS instrument type: Micromass ZQ; HPLC instrument type: HP1100Series; UV DAD; Post: Phenomenex Gemini 3 μ, 30mm × 3.0mm; Elutriant A:1L water+0.5ml 50% formic acid, elutriant B:1L acetonitrile+0.5ml 50% formic acid; Gradient: 0.0min 90%A → 2.5min 30%A → 3.0min 5%A → 4.5min 5%A; Flow velocity: 0.0min 1ml/min, 2.5min/3.0min/4.5min 2ml/min; Baking oven: 50 DEG C; UV detects: 210nm.
method 2B:instrument: the Micromass QuattroPremier with Waters UPLC Acquity; Post: Thermo Hypersil GOLD 1.9 μ, 50mm × 1mm; Elutriant A:1L water+0.5ml 50% formic acid, elutriant B:1L acetonitrile+0.5ml 50% formic acid; Gradient: 0.0min 90%A → 0.1min 90%A → 1.5min 10%A → 2.2min 10%A; Baking oven: 50 DEG C; Flow velocity: 0.33ml/min; UV detects: 210nm.
method 3B:mS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; Post: Phenomenex Synergi 2.5 μMs of AX-RP 100A Mercury, 20mm × 4mm; Elutriant A:1L water+0.5ml 50% formic acid, elutriant B:1L acetonitrile+0.5ml 50% formic acid; Gradient: 0.0min 90%A → 0.1min 90%A → 3.0min5%A → 4.0min 5%A → 4.01min 90%A; Flow velocity: 2ml/min; Baking oven: 50 DEG C; UV detects: 210nm.
method 4B:instrument: the Micromass Quattro Micro MS with HPLC Agilent Series 1100; Post: Thermo Hypersil GOLD 3 μ 20mm × 4mm; Elutriant A:1L water+0.5ml 50% formic acid, elutriant B:1L acetonitrile+0.5ml 50% formic acid; Gradient: 0.0min 100%A → 3.0min 10%A → 4.0min 10%A → 4.01min100%A → 5.00min 100%A; Baking oven: 50 DEG C; Flow velocity: 2ml/min; UV detects: 210nm.
method 5B:instrument: Waters Acquity SQD UPLC System; Post: Waters Acquity UPLC HSS T31.8 μ 50mm × 1mm; Elutriant A:1L water+0.25ml99% formic acid, elutriant B:1L acetonitrile+0.25ml 99% formic acid; Gradient: 0.0min 90%A → 1.2min 5%A → 2.0min 5%A; Baking oven: 50 DEG C; Flow velocity: 0.40ml/min; UV detects: 210-400nm.
method 6B:mS instrument type: Waters (Micromass) Quattro Micro; HPLC instrument type: Agilent 1100Series; Post: Thermo Hypersil GOLD 3 μ 20mm × 4mm; Elutriant A:1L water+0.5ml 50% formic acid, elutriant B:1L acetonitrile+0.5ml50% formic acid; Gradient: 0.0min 100%A → 3.0min 10%A → 4.0min 10%A → 4.01min 100%A; (flow velocity: 2.5ml/min) → 5.00min 100%A; Baking oven: 50 DEG C; Flow velocity: 2ml/min; UV detects: 210nm.
method 7B:mS instrument type: Waters ZQ; HPLC instrument type: Agilent 1100Series; UV DAD; Post: Thermo Hypersil GOLD 3 μ 20mm × 4mm; Elutriant A:1L water+0.5ml 50% formic acid, elutriant B:1L acetonitrile+0.5ml 50% formic acid; Gradient: 0.0min 100%A → 3.0min 10%A → 4.0min 10%A baking oven: 55 DEG C; Flow velocity: 2ml/min; UV detects: 210nm.
the preparative separation of enantiomer:
method 1D:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 20mm, elutriant: isohexane/Virahol 25: 75; Flow velocity: 15ml/min, temperature: 45 DEG C; UV detects: 220nm.
method 2D:phase: Daicel Chiralpak IA, 5 μm of 250mm × 20mm, elutriant: methyl alcohol/acetonitrile 25: 75; Flow velocity: 15ml/min, temperature: 30 DEG C; UV detects: 220nm.
method 3D:phase: Daicel Chiralpak IA, 5 μm of 250mm × 20mm, elutriant: methyl alcohol/acetonitrile 50: 50; Flow velocity: 15ml/min, temperature: 30 DEG C; UV detects: 220nm.
method 4D:phase: Daicel Chiralpak IA, 5 μm of 250mm × 20mm, elutriant: tert-butyl methyl ether/methyl alcohol 50: 50; Flow velocity: 15ml/min; Temperature: 30 DEG C; UV detects: 220nm.
method 5D:phase: Daicel Chiralpak IA, 5 μm of 250mm × 20mm, elutriant: methyl alcohol/acetonitrile 25: 75; Flow velocity: 15ml/min, temperature: 30 DEG C; UV detects: 220nm.
method 6D:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 20mm, elutriant: isohexane/ethanol 25: 75; Flow velocity: 15ml/min, temperature: 45 DEG C; UV detects: 220nm.
method 7D:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 20mm, elutriant: ethanol 100%; Flow velocity: 15ml/min, temperature: 45 DEG C; UV detects: 220nm.
method 8D:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 20mm, elutriant: isohexane/Virahol 30: 70; Flow velocity: 15ml/min, temperature: 45 DEG C; UV detects: 220nm.
method 9D:phase: Daicel Chiralpak IA, 5 μm of 250mm × 20mm, elutriant: acetonitrile/methanol 70: 30; Flow velocity: 15ml/min, temperature: 30 DEG C; UV detects: 220nm.
method 10D:phase: Daicel Chiralpak IA, 5 μm of 250mm × 20mm, elutriant: acetonitrile/methanol 70: 30; Flow velocity: 20ml/min, temperature: 35 DEG C; UV detects: 210nm.
method 11D:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 20mm, elutriant: isohexane/ethanol 70: 30; Flow velocity: 15ml/min, temperature: 40 DEG C; UV detects: 220nm.
the compartment analysis of enantiomer:
method 1E:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 4mm; Elutriant: Virahol/isohexane: 75:25; Flow velocity: 1ml/min; Temperature: 45 DEG C; UV detects: 220nm.
method 2E:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 4.6mm; Elutriant: isohexane/Virahol 25:75+0.2% trifluoroacetic acid+1% water; Flow velocity: 1ml/min; Temperature: 45 DEG C; UV detects: 235nm.
method 3E:phase: Daicel Chiralpak IA, 5 μm of 250mm × 4.6mm, elutriant: acetonitrile/methanol 75: 25; Flow velocity: 1ml/min; Temperature: 25 DEG C; UV detects: 220nm.
method 4E:phase: Daicel Chiralpak IA, 5 μm of 250mm × 4.6mm, elutriant: acetonitrile/methanol 50: 50; Flow velocity: 1ml/min; Temperature: 25 DEG C; UV detects: 220nm.
method 5E:phase: Daicel Chiralpak 1A, 5 μm of 250mm × 4.6mm, elutriant: tert-butyl methyl ether/methyl alcohol 50: 50; Flow velocity: 1ml/min; Temperature: 25 DEG C; UV detects: 220nm.
method 6E:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 4.6mm, elutriant: ethanol 100%; Flow velocity: 1ml/min, temperature: 45 DEG C; UV detects: 220nm.
method 7E:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 4.6mm, elutriant: isohexane/Virahol 30: 70; Flow velocity: 1ml/min, temperature: 45 DEG C; UV detects: 220nm.
method 8E:phase: Daicel Chiralpak IA, 5 μm of 250mm × 4.6mm, elutriant: acetonitrile/methanol 70: 30; Flow velocity: 15ml/min, temperature: 25 DEG C; UV detects: 220nm.
method 9E:phase: Daicel Chiralpak IA, 5 μm of 250mm × 4.6mm, elutriant: acetonitrile/methanol 70: 30; Flow velocity: 15ml/min, temperature: 30 DEG C; UV detects: 220nm.
method 10E:phase: Daicel Chiralpak IA, 5 μm of 250mm × 4.6mm, elutriant: acetonitrile/methanol 70: 30; Flow velocity: 1ml/min, temperature: 30 DEG C; UV detects: 220nm.
method 11E:phase: Daicel Chiralpak AD-H, 5 μm of 250mm × 4.6mm, elutriant: isohexane/ethanol 25: 75+0.2% trifluoroacetic acid+1% water; Flow velocity: 1ml/min, temperature: 45 DEG C; UV detects: 220nm.
gC-MS method:
method 1F:instrument: Micromass GCT, GC6890; Post: Restek RTX-35,15m × 200 μm × 0.33 μm; With helium constant current speed: 0.88ml/min; Baking oven: 70 DEG C; Import: 250 DEG C; Gradient: 70 DEG C, 30 DEG C/min → 310 DEG C (keeping 3min).
The microwave reactor used is Emrys tM" single mode " instrument of Optimizer type.
precursor compound
General method 1A:N '-hydroxyamidines is formed
Under RT, the solution of suitable nitrile (1.0 equivalent) in ethanol (1.2ml/mmol) mixes with hydroxylammonium chloride (1.5 equivalent) and triethylamine (1.2 equivalent).Reaction mixture at room temperature stirs and spends the night.In order to aftertreatment, under reduced pressure remove ethanol, add saturated sodium bicarbonate aqueous solution and reaction mixture ethyl acetate is extracted.Organic phase is also concentrated by dried over sodium sulfate.Resistates reacts without further purification.
General method 2A:N '-hydroxyamidines is formed
Under RT, the solution of suitable nitrile (1.0 equivalent) in the mixture of ethanol (1.9ml/mmol) and water (0.5ml/mmol) mixes with hydroxylammonium chloride (1.08 equivalent) and sodium hydroxide (1.12 equivalent).Reaction mixture at room temperature stirs 16 hours.In order to aftertreatment, reaction mixture under reduced pressure concentrates, and mixes and filter with methylene dichloride.Filtrate under reduced pressure concentrates and resistates reacts without further purification.
General method 3A:Suzuki coupling
Under argon and under RT, the mixture of suitable bromopyridine in toluene (1.8ml/mmol) and tetrakis triphenylphosphine palladium (0.02 equivalent), with the solution of suitable aryl boric acid (1.2 equivalent) in ethanol (0.5ml/mmol) with mix with Potassium monofluoride (2.0 equivalent) solution in water (0.2ml/mmol).Reaction mixture stirs several hours under reflux until transform substantially complete.After adding ethyl acetate and being separated, organic phase washed with water once and with saturated sodium-chloride water solution washs once, and dry (magnesium sulfate) filters and under reduced pressure concentrates.Crude product is by flash chromatography (silica gel 60, elutriant: methylene chloride/methanol mixture).
General method 4A: the hydrogenation of pyridine
Under argon, the solution of pyridine in ethanol (9ml/mmol) and palladium (with about 50% water-wet, 0.3g/mmol) on activated carbon mix, and mixture at 60 DEG C in 50 bar nitrogen atmosphere hydrogenated over night.Then filter catalyzer by filtering layer and repeatedly use washing with alcohol.The filtrate merged under reduced pressure concentrates.
General method 5A: methyl esters hydrolysis/epimerization
Under RT, in the solution of suitable methyl esters (1.0 equivalent) in methyl alcohol (35-40ml/mmol), add uncle-butanols potassium (10 equivalent).Mixture stirs and spends the night at 60 DEG C.If transformed not exclusively, add water (1.0 equivalent) and mixture stirs until transform complete at 60 DEG C.In order to aftertreatment, under reduced pressure remove methyl alcohol, resistates mixes with water and mixture 1N aqueous hydrochloric acid acidifying (pH 1).Mixture ethyl acetate is extracted and organic phase dried over mgso, filters and under reduced pressure concentrates.
General method 6A: diazole is formed
Under argon, under RT, the solution of suitable piperidines-3-carboxylic acid in dimethyl formamide (10-20ml/mmol) and HATU (1.2 equivalent), DIPEA (2.2 equivalent) and suitable N '-hydroxyamidines (1.1 equivalent) mixing.Reaction mixture stirs under RT until the formation of intermediate completes and then stir until formed the product wanted by this intermediate at 120 DEG C further.Then reaction mixture is purified by preparative HPLC.
embodiment 1A
N '-hydroxy-3-methoxy third amidine
React according to general method 1A, 20.0g (235.0mmol) 3-methoxypropionitrile.Productive rate: 18.1g (theoretical 49%, purity 74%)
HPLC (method 1A): R t=0.35min; MS (ESIpos): m/z=119 [M+H] +.
embodiment 2A
3-oxyethyl group-N '-hydroxyl third amidine
React according to general method 2A, 5.0g (50.4mmol) 3-ethoxy propionitrile.Productive rate: 0.6g (theoretical 8%, purity 90%)
HPLC (method 1A): R t=0.60min; MS (ESIpos): m/z=133 [M+H] +.
embodiment 3A
N '-hydroxyl cyclopropane-1-carboximidamide
React according to general method 2A, 7.2g (107.3mmol) cyclopropanecarbonitrile.Productive rate: 4.8g (theoretical 44%)
LC-MS (method 2B): R t=0.16min; MS (ESIpos): m/z=101 [M+H] +.
embodiment 4A
5-(4-ethylphenyl) pyridine-3-carboxylic acid methyl esters
According to general method 3A, 32g (148mmol) 5-bromo-nicotinic acid methyl esters and 27g (178mmol, 1.2 equivalents) 4-ethylphenyl acid reaction.Productive rate: 24g (theoretical 64%)
LC-MS (method 3B): R t=2.03min; MS (ESIpos): m/z=242 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝9.13(d，1H)，9.05(d，1H)，8.45(t，1H)，7.72(d，2H)，7.38(d，2H)，3.93(s，3H)，2.68(q，2H)，1.22(t，3H)。
embodiment 5A
5-(4-ethylphenyl) piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
According to general method 4A, hydrogenation 24g (94mmol) 5-(4-ethylphenyl) pyridine-3-carboxylic acid methyl esters.Productive rate: 20g (theoretical 77%)
LC-MS (method 4B): R t=1.43min; MS (ESIpos): m/z=248 [M+H] +.
embodiment 6A
5-(4-ethylphenyl)-1-(thiomorpholine-4-base carbonyl) piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
5.00g (12.1mmol) 5-(4-ethylphenyl) piperidines-1 is added in 76ml DMF, 3-dicarboxylic acid 3-methyl isophthalic acid-(4-oil of mirbane) ester (embodiment 30A), 3.57g (36.4mmol) thiomorpholine and 5.03g (36.4mmol) salt of wormwood and be divided into 5 parts at 150 DEG C, heat 1.5h in single mold microwave device (Emrys Optimizer).In order to aftertreatment, merge reaction soln and filter, and resistates is purified by preparative HPLC.Productive rate: 3.07g (theoretical 67%)
LC-MS (method 5B): R t=1.16 and 1.18min (cis/trans isomer); MS (ESIpos): m/z=377 [M+H] +.
embodiment 7A
5-(4-ethylphenyl)-1-(thiomorpholine-4-base carbonyl) piperidines-3-carboxylic acid [cis-isomeride of racemization]
According to general method 5A, 3.00g (7.97mmol) from the compound of embodiment 6A and the reaction of 8.94g (79.7mmol) potassium tert.-butoxide.This reaction preference ground produces cis-isomeride.Productive rate: 2.74g (theoretical 93%)
LC-MS (method 5B): R t=1.04min; MS (ESIpos): m/z=363 [M+H] +.
embodiment 8A
{ 3-(4-ethylphenyl)-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 300mg (0.828mmol) from the compound of embodiment 7A and the reaction of 134mg (0.910mmol) N '-hydroxy-3-methoxy third amidine.Productive rate: 185mg (theoretical 49%)
LC-MS (method 5B): R t=1.22min; MS (ESIpos): m/z=445 [M+H] +.
embodiment 9A
[3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-(4-ethylphenyl) piperidin-1-yl] (thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 300mg (0,828mmol) from the compound of embodiment 7A and 91mg (0.91mmol) N '-hydroxyl cyclopropane-1-carboximidamide reaction.Productive rate: 141mg (theoretical 40%)
LC-MS (method 5B): R t=1.32min; MS (ESIpos): m/z=427 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.22(d，2H)，7.15(d，2H)，3.92(d，1H)，3.52(d，1H)，3.44(br.s.，4H)，3.38-3.31(m，1H)，3.03-2.79(m，3H)，2.63-2.55(m，6H)，2.25(d，1H)，2.10(td，1H)，1.91(q，1H)，1.16(t，3H)，1.09-1.01(m，2H)，0.92-0.85(m，2H)。
embodiment 10A
{ 3-(4-ethylphenyl)-5-[3-(2-hydroxyethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 300mg (0.828mmol) from the compound of embodiment 7A and 112mg (1.08mmol) N ', 3-dihydroxyl third amidine [Graham A.Showell etc., J.Med.Chem., 1991,34,1086-1094] reaction.Productive rate: 248mg (theoretical 66%)
LC-MS (method 5B): R t=2.22min; MS (ESIpos): m/z=431 [M+H] +.
embodiment 11A
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-(4-ethylphenyl) piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 600mg (1.655mmol) from the compound of embodiment 7A and the reaction of 355mg (about 2.152mmol) 3-oxyethyl group-N '-hydroxyl third amidine.Productive rate: 389mg (theoretical 49%)
LC-MS (method 6B): R t=2.61min; MS (ESIpos): m/z=459 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.23(d，2H)，7.16(d，2H)，3.95(d，1H)，3.71(t，2H)，3.54(d，1H)，3.48-3.34(m，7H)，3.08-2.81(m，5H)，2.63-2.55(m，6H)，2.29(d，1H)，1.95(q，1H)，1.16(t，3H)，1.07(t，3H)。
embodiment 12A
5-[4-(trifluoromethyl) phenyl] pyridine-3-carboxylic acid methyl esters
According to general method 3A, 28g (132mmol) 5-bromo-nicotinic acid methyl esters and the reaction of 30g (158mmol, 1.2 equivalents) 4-trifluoromethyl phenyl boronic acid.Productive rate: 32g (theoretical 85%)
LC-MS (method 4B): R t=2.27min; MS (ESIpos): m/z=282 [M+H] +.
embodiment 13A
5-[4-(trifluoromethyl) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
According to general method 4A, hydrogenation 32g (112mmol) 5-[4-(trifluoromethyl) phenyl] pyridine-3-carboxylic acid methyl esters (embodiment 12A).Productive rate: 26g (theoretical 82%)
LC-MS (method 1B): R t=1.35 and 1.41min (cis/trans isomer); MS (ESIpos): m/z=288 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝9.22(d，1H)，9.14(d，1H)，8.57(t，1H)，8.06(d，2H)，7.89(d，2H)，3.94(s，3H)。
embodiment 14A
5-[4-(trifluoromethyl) phenyl] piperidines-1,3-dicarboxylic acid 3-methyl isophthalic acid-(4-oil of mirbane) ester [the cis/trans isomer mixture of racemization]
20.0g (69.6mmol) 5-[4-(trifluoromethyl) phenyl] piperidines-3-carboxylate methyl ester (embodiment 13A) is dissolved in 1.01 methylene dichloride, and mixes with 14.1g (139mmol) triethylamine at 0 DEG C.Subsequently, 14.0g (69.6mmol) chlorine carbonic acid 4-nitro phenyl ester is dripped.Reaction mixture stirs 2h and then under RT, stirs 16h at 0 DEG C.In order to aftertreatment, the saturated sodium bicarbonate aqueous solution of mixture washs.Organic phase, by dried over mgso, is filtered and under reduced pressure concentrates.This produces 31.3g crude product, and it does not react with having further purification step.
LC-MS (method 3B): R t=2.44min and 2.48min (cis/trans isomer); MS (ESIpos): m/z=453 [M+H] +.
embodiment 15A
1-(thiomorpholine-4-base carbonyl)-5-[4-(trifluoromethyl) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
10.0g (22.1mmol) 5-[4-(trifluoromethyl) phenyl] piperidines-1 is added in 150ml DMF, 3-dicarboxylic acid 3-methyl isophthalic acid-(4-oil of mirbane) ester, 6.84g (66.3mmol) thiomorpholine and 9.17g (66.3mmol) salt of wormwood and be divided into 10 parts at 150 DEG C in single mold microwave device (Emrys Optimizer) heating 1h.In order to aftertreatment, merge reaction soln and filter, and resistates is purified by preparative HPLC.Productive rate: 5.16g (theoretical 55%)
LC-MS (method 5B): R t=1.13 and 1.16min (cis/trans isomer); MS (ESIpos): m/z=417 [M+H] +.
embodiment 16A
1-(thiomorpholine-4-base carbonyl)-5-[4-(trifluoromethyl) phenyl] piperidines-3-carboxylic acid [cis-isomeride of racemization]
According to general method 5A, 5.16g (12.4mmol) from the compound of embodiment 15A and the reaction of 13.9g (124mmol) potassium tert.-butoxide.This reaction preference ground produces cis-isomeride.Productive rate: 4.90g (theoretical 98%)
LC-MS (method 5B): R t=1.04min; MS (ESIpos): m/z=403 [M+H] +.
embodiment 17A
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 600mg (1.491mmol) from the compound of embodiment 16A and 164mg (0.164mmol) N '-hydroxyl cyclopropane-1-carboximidamide reaction.Productive rate: 352mg (theoretical 47%)
LC-MS (method 5B): R t=1.28min; MS (ESIpos): m/z=467 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.56(d，2H)，3.92(d，1H)，3.57(d，1H)，3.45(br.s.，4H)，3.40-3.34(m，1H)，3.08-2.95(m，3H)，2.59(br.s.，4H)，2.30(d，1H)，2.16-2.07(m，1H)，2.04-1.91(m，1H)，1.10-1.01(m，2H)，0.92-0.85(m，2H)。
embodiment 18A
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 600mg (1.491mmol) from the compound of embodiment 16A and the reaction of 242mg (1.640mmol) N '-hydroxy-3-methoxy third amidine.Productive rate: 350mg (theoretical 46%)
LC-MS (method 5B): R t=1.18min; MS (ESIpos): m/z=485 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.57(d，2H)，3.95(d，1H)，3.68(t，2H)，3.58(d，1H)，3.51-3.36(m，5H)，3.23(s，3H)，3.13-2.96(m，3H)，2.94(t，2H)，2.60(br.s.，4H)，2.33(br.d.，1H)，2.10-1.95(m，1H)。
embodiment 19A
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 600mg (1.491mmol) from the compound of embodiment 16A and the reaction of 320mg (about 1.983mmol) 3-oxyethyl group-N '-hydroxyl third amidine.Productive rate: 343mg (theoretical 46%)
LC-MS (method 6B): R t=2.57min; MS (ESIpos): m/z=499 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.57(d，2H)， 3.96(d，1H)，3.71(t，2H)，3.58(d，1H)，3.49-3.37(m，7H)，3.11-2.97(m，3H)，2.93(t，2H)，2.60(br.s.，4H)，2.34(br.d.，1H)，2.02(q，1H)，1.07(t，3H)。
embodiment 20A
{ 3-[3-(2-hydroxyethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 600mg (1.491mmol) from the compound of embodiment 16A and the reaction of 201mg (1.938mmol) N ', 3-dihydroxyl third amidine.Productive rate: 494mg (theoretical 68%)
LC-MS (method 5B): R t=1.04min; MS (ESIpos): m/z=471 [M+H] +.
embodiment 21A
5-[4-(trifluoromethoxy) phenyl] pyridine-3-carboxylic acid methyl esters
According to general method 3A, 23g (105mmol) 5-bromo-nicotinic acid methyl esters and 26g (126mmol, 1.2 equivalents) 4-Trifluoromethoxyphen-l acid reaction.Productive rate: 14g (theoretical 41%)
LC-MS (method 1B): R t=2.44min; MS (ESIpos): m/z=298 [M+H] +.
Other synthesis method:
Under argon, under RT, the solution of 26g (121mmol) 5-bromo-nicotinic acid methyl esters in toluene (220ml) mixes with 2.8g (2.4mmol) tetrakis triphenylphosphine palladium, and then adds the solution of 30g (146mmol) 4-Trifluoromethoxyphen-l boric acid in ethanol (58ml).After being added in 14g (243mmol) Potassium monofluoride in water (58ml), mixture stirs under reflux and spends the night, add 0.70g (0.61mmol) tetrakis triphenylphosphine palladium further, and mixture stirs 24h under reflux again.After adding 1.4g (1.2mmol) tetrakis triphenylphosphine palladium again, mixture stirs 20h under reflux, and reaction soln mixes with ethyl acetate and uses water and saturated aqueous NaCl wash.Organic phase, by dried over mgso, is filtered and under reduced pressure concentrates.Resistates purifies (silica gel, hexanaphthene/methylene dichloride 1: 1 → methylene dichloride) by column chromatography.Productive rate: 31g (theoretical 86%)
LC-MS (method 4B): R t=2.32min; MS (ESIpos): m/z=298 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝9.17(d，1H)，9.10(d，1H)，8.51(t，1H)，7.95(d，2H)，7.52(d，2H)，3.94(s，3H)。
embodiment 22A
5-[4-(trifluoromethoxy) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
Palladium/carbon catalyst (10% palladium that 14g (45mmol) 5-[4-(trifluoromethoxy) phenyl] pyridine-3-carboxylic acid methyl esters in ethanol (500ml) and 17g soak, 50% water) mixing, and then at 60 DEG C and 50 bar nitrogen atmosphere under hydrogenated over night.Filtering reacting solution, filter residue washing with alcohol under reduced pressure concentrated filtrate.Resistates purifies (silica gel, methylene chloride/methanol 600: 1 → 10: 1) by column chromatography.Productive rate: 8g (theoretical 59%)
LC-MS (method 1B): R t=1.29min and 1.33min (cis/trans isomer); MS (ESIpos): m/z=304 [M+H] +;
1h NMR (400MHz, DMSO-d 6): δ=7.43-7.35 (m, 4H), 7.31-7.25 (m, 4H), 3.60 (s, 3H), 3.40-3.21 (m, 5H), 3.16 (d, 1H), 3.01-2.89 (m, 3H), 2.88-2.78 (m, 2H), 2.78-2.65 (m, 4H), 2.17 (d, 1H), 2.09 (d, 1H), 1.82 (td, 1H), 1.68 (q, 1H), about 1: 1.3 mixture of cis/trans isomer, two hiding protons.
embodiment 23A
5-[4-(trifluoromethoxy) phenyl] piperidines-1,3-dicarboxylic acid 3-methyl isophthalic acid-(4-oil of mirbane) ester [the cis/trans isomer mixture of racemization]
At 0 DEG C, slowly in 8.0g (26.4mmol) 5-[4-(trifluoromethoxy) phenyl] piperidines-3-carboxylate methyl ester (embodiment 22A) in 666ml methylene fluoride and 5.34g (26.3mmol) triethylamine, add 5.32g (26.4mmol) chloroformic acid 4-nitro phenyl ester.Mixture stirs 2h under RT.In order to aftertreatment, first reaction mixture with the washing of saturated sodium bicarbonate aqueous solution, then washes with water.Organic phase is also under reduced pressure concentrated by dried over sodium sulfate.Resistates is by purifying (elutriant: cyclohexane/ethyl acetate 1: 2 → 1: 1) at flash chromatography on silica gel.Productive rate: 7.32g (theoretical 54%)
LC-MS (method 3B): R t=2.47min; MS (ESIpos): m/z=469 [M+H] +.
embodiment 24A
1-(thiomorpholine-4-base carbonyl)-5-[4-(trifluoromethoxy) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
12.0g (25.1mmol) 5-[4-(trifluoromethoxy) phenyl] piperidines-1 is added in 180ml DMF, 3-dicarboxylic acid 3-methyl isophthalic acid-(4-oil of mirbane) ester, 7.77g (75.3mmol) thiomorpholine and 10.4g (75.3mmol) salt of wormwood are also divided into 12 parts at 150 DEG C, heat 2h in single mold microwave devices (Emrys Optimizer).In order to aftertreatment, merge reaction soln and filter, and resistates is purified by preparative HPLC.Productive rate: 7.88g (theoretical 73%)
LC-MS (method 5B): R t=1.16 and 1.18min (cis/trans isomer); MS (ESIpos): m/z=433 [M+H] +.
1h NMR (400MHz, DMSO-d 6): δ=7.46-7.39 (m, 4H), 7.32 (d, 4H), 3.84 (dd, 2H), 3.64 (s, 3H), 3.63 (s, 3H), 3.55-3.34 (m, 10H), 3.09 (dd, 1H), 3.06-2.96 (m, 1H), 2.92-2.81 (m, 6H), 2.76-2.67 (m, 1H), 2.65-2.56 (m, 7H), 2.25-2.10 (m, 2H), 1.95-1.84 (m, 1H), 1.76 (q, 1H), about 1: 1 mixture of cis/trans isomer.
embodiment 25A
1-(thiomorpholine-4-base carbonyl)-5-[4-(trifluoromethoxy) phenyl] piperidines-3-carboxylic acid [the cis/trans isomer mixture of racemization]
Under RT, add 20.4g (182ml) potassium tert.-butoxide to 7.85g (18.2mmol) from solution in methyl alcohol (650ml) of the compound of embodiment 24A.Mixture stirs and spends the night at 60 DEG C.In order to aftertreatment, under reduced pressure remove methyl alcohol, resistates mixes with water and mixture 1N aqueous hydrochloric acid acidifying (pH=1).Mixture ethyl acetate is extracted, and organic phase dried over mgso, filter and under reduced pressure concentrate.This reaction produces 85: 15 cis/trans isomer mixtures.Productive rate: 7.70g (theoretical 99%)
LC-MS (method 5B): R t=1.03 (trans-isomer(ide)s) and 1.04min (cis-isomeride); MS (ESIpos): m/z=419 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝12.44(br.s.，1H)，7.47-7.39(m，2H)，7.31(d，2H)，3.79(d，1H)，3.56-3.48(m，1H)，3.46-3.37(m，4H)，2.91-2.73(m，3H)，2.63-2.55(m，5H)，2.14(d，1H)，1.81-1.66(m，1H)。
embodiment 26A
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 600mg (1.43mmol) from the compound of embodiment 25A and the reaction of 232mg (1.58mmol) N '-hydroxy-3-methoxy third amidine.Productive rate: 398mg (theoretical 53%)
LC-MS (method 5B): R t=1.21min; MS (ESIpos): m/z=501 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.47(d，2H)，7.33(d，2H)，3.95(d，1H)，3.68(t，2H)，3.56(d，1H)，3.50-3.35(m，5H)，3.23(s，3H)，3.08-2.86(m，5H)，2.60(br.s.，4H)，2.32(d，1H)，1.97(q，3H)。
embodiment 27A
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 300mg (0.717mmol) from the compound of embodiment 25A and 79mg (0.789mmol) N '-hydroxyl cyclopropane-1-carboximidamide reaction.Productive rate: 135mg (theoretical 39%)
LC-MS (method 2B): R t=1.44min; MS (ESIpos): m/z=483 [M+H] +.
Other synthesis method:
Under RT, 600mg (1.43mmol) in dimethyl formamide (29.0ml) is from the compound of embodiment 25A and 654mg (1.72mmol) HATU and 0.55ml (498mg, 3.16mmol) N, N-diisopropylethylamine mixes, and mixture stirs 30min.Subsequently, 158mg (1.58mmol) N '-hydroxyl cyclopropane-1-carboximidamide is added and mixture stirs and spends the night under RT.Reaction soln is heated to 120 DEG C and stirs 1h at such a temperature.Reaction soln is direct is subsequently purified by preparative HPLC.Productive rate: 315mg (theoretical 45%)
LC-MS (method 5B): R t=1.30min; MS (ESIpos): m/z=483 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.46(d，2H)，7.33(d，2H)，3.91(d，1H)，3.55(d，1H)，3.45(br.s.，4H)，3.39-3.32(m，1H)，3.05-2.91(m，3H)，2.59(br.s.，4H)，2.28(d，1H)，2.17-2.08(m，1H)，1.93(q，1H)，1.10-1.02(m，2H)，0.92-0.84(m，2H)。
embodiment 28A
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 600mg (1.434mmol) from the compound of embodiment 25A and the reaction of 307mg (about 1.864mmol) 3-oxyethyl group-N '-hydroxyl third amidine.Productive rate: 403mg (theoretical 55%)
LC-MS (method 6B): R t=2.61min; MS (ESIpos): m/z=515 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.47(d，2H)，7.33(d，2H)，3.95(d，1H)，3.71(t，2H)，3.56(d，1H)，3.50-3.35(t，7H)，3.10-2.88(m，5H)，2.60(br.s.，4H)，2.32(d，1H)，2.02-1.92(m，1H)，1.07(t，3H)。
embodiment 29A
{ 3-[3-(2-hydroxyethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 1.00g (2.390mmol) from the compound of embodiment 25A and the reaction of 323mg (3.107mmol) N ', 3-dihydroxyl third amidine.Productive rate: 848mg (theoretical 69%)
LC-MS (method 6B): R t=2.26min; MS (ESIpos): m/z=487 [M+H] +.
embodiment 30A
5-(4-ethylphenyl) piperidines-1,3-dicarboxylic acid 3-methyl isophthalic acid-(4-oil of mirbane) ester [the cis/trans isomer mixture of racemization]
Start in 30ml methylene dichloride, add the compound of 3.0g (12.1mmol) from embodiment 5A, be cooled to 0 DEG C and mix with 3.4ml (2.4g, 12.1mmol) triethylamine and 2.4g (12.1mmol) chloroformic acid 4-nitre phenyl ester.Make reaction mixture slowly warm up RT and stir 16h under RT.Mixture washes with water several times, by dried over sodium sulfate, filters and under reduced pressure concentrates.Resistates is by purifying (eluent dichloromethane → methylene chloride/methanol 100: 2) at silica gel Column chromatography.Productive rate: 4.7g (theoretical 83%, purity 89%)
HPLC (method 1A): R t=4.94min and 5.00min (cis/trans isomer); MS (ESIpos): m/z=413 [M+H] +.
embodiment 31A
Thiomorpholine-4-carboxylic acid 4-nitro phenyl ester
Start in 100ml methylene dichloride, add 7.7g (74.4mmol) thiomorpholine and, with being cooled with an ice bath, mix with 20.7ml (15.1g, 148.8mmol) triethylamine.Add 10.0g (49.6mmol) chloroformic acid 4-nitro phenyl ester in batches.Reaction mixture stirs one hour under RT, mixes with water and ethyl acetate.Removing organic phase, with 1N hydrochloric acid and saturated aqueous NaCl wash, by dried over sodium sulfate, filters and under reduced pressure concentrates.Productive rate: 13.2g (theoretical 99%)
LC-MS (method 5B): R t=0.98min; MS (ESIpos): m/z=269 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝8.28(d，2H)，7.46(d，2H)，3.86(br.s.，2H)，3.72(br.s.，2H)，2.71(br.d.，4H)。
embodiment 32A
Thiomorpholine-4-carboxylic acid 4-nitro phenyl ester 1-oxide compound
Start in 135ml methylene dichloride, add 13.1g (49.0mmol) thiomorpholine-4-carboxylic acid 4-nitro phenyl ester and at 0 DEG C with 7.6g (44.1mmol) m-chlorine peroxybenzoic acid batch mixing.Mixture stirs two hours under RT, adds water and removes organic phase.Organic phase with the washing of saturated sodium bicarbonate aqueous solution, is filtered and under reduced pressure concentrates rapidly.Crude product is purified by preparative HPLC.Productive rate: 7.8g (theoretical 56%)
LC-MS (method 5B): R t=0.69min; MS (ESIpos): m/z=285 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝8.30(d，2H)，7.49(d，2H)， 4.20-3.70(m，4H)，3.03(dt，2H)，2.85(d，2H)。
embodiment 33A
[5-(methoxycarbonyl) pyridin-3-yl] borate hydrochlorate
Start under argon, in 375ml DMF, add 17.6g (81.4mmol) 5-bromo-nicotinic acid methyl esters and with 26.9g (105.8mmol) 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-bis--1,3,2-dioxaborolan, 3.0g (3.6mmol) three (dibenzalacetone) two palladium (0), 1.8g (6.5mmol) tricyclohexyl phosphine and the mixing of 32.0mmol (325.9mmol) potassium acetate.Reaction mixture stirs 20h at 100 DEG C.Subsequently, under reduced pressure except desolventizing, resistates mixes with 40ml water and 140ml tert-butyl methyl ether, and removes organic phase.Extract three times with the tert-butyl methyl ether of 80ml containing aqueous phase at every turn.The organic extraction saturated sodium-chloride water solution merged washs, and by dried over mgso, filters and concentrates.Resistates absorbs and mixes with 36ml concentrated hydrochloric acid in 360ml methyl alcohol.Reaction mixture reflux 22h and then stir 12h under RT.Under reduced pressure remove only about half of solvent, and filtering solution and under reduced pressure concentrating further.Oily resistates by acetone recrystallize twice, and absorbs and mixes with 100ml tert-butyl methyl ether in 10ml acetone.After 16h, removed the precipitation formed by solution.This is deposited in 50ml acetone and stirs and under RT static 5 weeks, and again removes solution.Merge solution, concentrate and dissolve in 50ml tert-butyl methyl ether.Mixture under RT static 5 weeks and then remove precipitation.This precipitation tert-butyl methyl ether washs three times and under reduced pressure drying in loft drier.
LC-MS (method 4B): R t=0.91min; MS (ESIpos): m/z=182 [M+H] +.
embodiment 34A
5-[4-(difluoro-methoxy) phenyl] nicotinic acid methyl ester
Reaction is reacted according to general method 3A, 10.0g (44.8mmol) 4-(difluoro-methoxy) bromination benzene and 14.6g (67.3mmol) [5-(methoxycarbonyl) pyridin-3-yl] borate hydrochlorate.Being released through of hydrochloride is added 6.80g (49.3mmol) salt of wormwood in addition and is completed.Productive rate: 8.6g (theoretical 67%)
LC-MS (method 2B): R t=1.15min; MS (ESIpos): m/z=280 [M+H] +.
embodiment 35A
5-[4-(difluoro-methoxy) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
The solution of 8.6g (30.9mmol) 5-[4-(difluoro-methoxy) phenyl] nicotinic acid methyl ester in spirit acid (112ml) mixes with 841mg palladium/carbon (10% palladium) and 1.12g platinum oxide (IV).This is succeeded by hydrogenation 24h under standard pressure under a hydrogen atmosphere.Reaction soln under reduced pressure concentrates.Resistates absorbs in water, with 1N hcl acidifying (pH1), by ether extraction, then alkalizes (pH > 10) with saturated sodium bicarbonate aqueous solution and repeatedly extracts by ethyl acetate.The filtrate merged, by dried over sodium sulfate, is filtered and under reduced pressure concentrates.Productive rate: 6.6g (theoretical 74%)
LC-MS (method 5B): R t=0.65min and 0.66min (cis/trans isomer); MS (ESIpos): m/z=286 [M+H] +.
embodiment 36A
5-[4-(difluoro-methoxy) phenyl]-1-[(1,1-dioxothiomorpholin-4-base) carbonyl] piperidines-3-carboxylate methyl ester [cis/trans isomer mixture]
2.2g (7.7mmo1) 5-[4-(difluoro-methoxy) phenyl] piperidines-3-carboxylate methyl ester is dissolved in 14ml N-Methyl pyrrolidone, and with 4.0ml (3.0g, 23.0mmol) N, N-diisopropylethylamine and the mixing of 3.5g (11.5mmol) thiomorpholine-4-carboxylic acid 4-nitro phenyl ester 1,1-dioxide.Reaction mixture reacts seven minutes in microwave at 180 DEG C.Subsequently, add water and ethyl acetate, and removing contains aqueous phase and repeatedly extracts by ethyl acetate.The organic extraction water merged and saturated aqueous NaCl wash, by dried over sodium sulfate, filter and under reduced pressure concentrate.Resistates absorbs and filters in ether, and filtrate is purified by preparative HPLC.Productive rate: 2.0g (theoretical 51%)
LC-MS (method 5B): R t=0.92min and 0.94min (cis/trans isomer); MS (ESIpos): m/z=447 [M+H] +.
embodiment 37A
5-[4-(difluoro-methoxy) phenyl]-1-[(1,1-dioxy thiomorpholine-4-base) carbonyl] piperidines-3-carboxylic acid [cis mixtures of isomers of racemization]
According to general method 4A, 2.7g (6.1mmol) 5-[4-(difluoro-methoxy) phenyl]-1-[(1,1-dioxothiomorpholin-4-base) carbonyl] piperidines-3-carboxylate methyl ester and 6.9g (61.3mmol) uncle-butanols nak response.Productive rate: 2.1g (theoretical 77%)
LC-MS (method 5B): R t=0.82min; MS (ESIpos): m/z=433 [M+H] +.
embodiment 38A
5-[4-(difluoro-methoxy) phenyl]-1-[(1-oxo thiomorpholine-4-base) carbonyl] piperidines-3-carboxylate methyl ester [cis/trans isomer mixture]
2.2g (7.7mmol) 5-[4-(difluoro-methoxy) phenyl] piperidines-3-carboxylate methyl ester is dissolved in 14ml N-Methyl pyrrolidone, and with 4.0ml (3.0g, 23.0mmol) DIPEA and the mixing of 3.5g (11.5mmol) thiomorpholine-4-carboxylic acid 4-nitro phenyl ester 1-oxide compound.Reaction mixture reacts seven minutes in microwave at 180 DEG C.Subsequently, add water and ethyl acetate, and removing contains aqueous phase and repeatedly extracts by ethyl acetate.The organic extraction water merged and saturated aqueous NaCl wash, by dried over sodium sulfate, filter and under reduced pressure concentrate.Resistates is purified by preparative HPLC.Productive rate: 2.2g (theoretical 59%)
LC-MS (method 5B): R t=0.90min and 0.92min (cis/trans isomer); MS (ESIpos): m/z=431 [M+H] +.
embodiment 39A
5-[4-(difluoro-methoxy) phenyl]-1-[(1-oxo thiomorpholine-4-base) carbonyl] piperidines-3-carboxylic acid [cis mixtures of isomers of racemization]
According to general method 4A, 2.7g (6.3mmol) 5-[4-(difluoro-methoxy) phenyl]-1-[(1-oxo thiomorpholine-4-base) carbonyl] piperidines-3-carboxylate methyl ester and 7.1g (63.3mmol) uncle-butanols nak response.Reaction mixture under reduced pressure concentrates, and resistates is suspended in water and uses concentrated hydrochloric acid acidifying.Filter precipitation, wash with water and drying under reduced pressure.Productive rate: 1.1g (theoretical 34%)
LC-MS (method 5B): R t=0.75min; MS (ESIpos): m/z=417 [M+H] +.
embodiment 40A
The bromo-4-of 1-(2,2,2-trifluoroethyl) benzene
Under RT, the solution of 25.0g (100mmol) 4-bromo benzyl bromo in 1-Methyl-2-Pyrrolidone (121ml) mixes with 4.95g (26.0mmol) cuprous iodide (I) and the fluoro-2-of 37.5g (195mmol) 2,2-bis-(fluorine sulphonyl) methyl acetate.Mixture be heated to 80 DEG C and then stir spend the night.Xiang Shuizhong adds reaction soln and uses ether extraction, and organic phase passes through dried over sodium sulfate.After organic phase is under reduced pressure filtered and concentrated, resistates purifies (silica gel, cyclohexane/ethyl acetate 20: 1) by column chromatography.Productive rate: 16.1g (theoretical 67%)
GC-MS (method 1F): R t=2.66min; MS (ESIpos): m/z=240 [M+H] +.
embodiment 41A
5-[4-(2,2,2-trifluoroethyl) phenyl] nicotinic acid methyl ester
Under argon, under RT, 8.00g (33.5mmol) mixes from the compound of embodiment 33A and 5.10g (36.8mmol) salt of wormwood with the 10.9g (50.2mmol) in ethanol (100ml) in the solution of toluene (304ml) from the compound of embodiment 40A.After stirring 10min, add 3.87g (3.35mmol) tetrakis triphenylphosphine palladium and 5.83g (100mmol) Potassium monofluoride then in water (64ml).Mixture stirs 8h under reflux, and cooled reaction solution and use diluted ethyl acetate.Reaction soln washs in water, and organic phase is by dried over mgso, filters and under reduced pressure concentrates.Resistates purifies (silica gel, methylene chloride/methanol 100: 1 → 80: 1) by column chromatography.Productive rate: 9.20g (theoretical 69%, purity 75%)
LC-MS (method 5B): R t=1.06min; MS (ESIpos): m/z=296 [M+H] +.
embodiment 42A
5-[4-(2,2,2-trifluoroethyl) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
9.20g (23.4mmol) mixes with 1.94g palladium/carbon (10% palladium) and 2.23g platinum oxide (IV) from the solution of compound in spirit acid (192ml) of embodiment 41A.This succeeded by hydrogenation 6h under standard pressure under a hydrogen atmosphere, and then adds 1.00g palladium/carbon (10% palladium) and 2.00g platinum oxide (IV), and hydrogenated over night under standard pressure under a hydrogen atmosphere.Subsequently, 1.00g palladium/carbon (10% palladium) and 3.00g platinum oxide (IV) is added further.Implement hydrogenation 24h more under standard pressure under a hydrogen atmosphere.Reaction soln is by diatomite filtration, and filter residue methanol/water is washed and the filtrate merged under reduced pressure concentrates.Resistates absorbs and then washs with 1N aqueous sodium carbonate in methylene dichloride.Organic phase, by dried over sodium sulfate, is filtered and under reduced pressure concentrates.Productive rate: 6.64g (theoretical 85%, purity 90%)
LC-MS (method 2B): R t=0.83 and 0.84min (cis/trans isomer); MS (ESIpos): m/z=302 [M+H] +.
embodiment 43A
5-[4-(2,2,2-trifluoroethyl) phenyl] piperidines-1,3-dicarboxylic acid 3-methyl isophthalic acid-(4-oil of mirbane) ester [the cis/trans isomer mixture of racemization]
6.62g (19.8mmol, purity 90%) mix from solution in methylene dichloride (211ml) of the compound of embodiment 42A and 9.65ml (7.00g, 69.2mmol) triethylamine and then mix with 3.99g (19.8mmol) fluorine formic acid 4-nitro phenyl ester at 0 DEG C.Mixture warms up RT and stirs 1h.Reaction soln saturated sodium bicarbonate aqueous solution and water washing, and organic phase is by dried over mgso, filters and under reduced pressure concentrates.Productive rate: 10.3g (theoretical 91%, purity 81%)
LC-MS (method 2B): R t=1.40 and 1.42min (cis/trans isomer); MS (ESIpos): m/z=467 [M+H] +.
embodiment 44A
1-(thiomorpholine-4-base carbonyl)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
10.3g (17.9mmol, purity 81%) from solution in 1-Methyl-2-Pyrrolidone (65ml) of the compound of embodiment 43A and 12.6ml (13.7g, 132mmol) thiomorpholine and 11.5ml (8.56g, 66.2mmol) DIPEA mixing and be then divided into 5 parts heat 1h at 150 DEG C in single mold microwave device (Emrys Optimizer).In order to aftertreatment, merge reaction soln and directly purified by preparative HPLC.Productive rate: 5.63g (theoretical 71%)
LC-MS (method 5B): R t=1.13and 1.16min (cis/trans isomers); MS (ESIpos): m/z=431 [M+H] +.
embodiment 45A
1-(thiomorpholine-4-base carbonyl)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidines-3-carboxylic acid [cis-isomeride of racemization]
Under RT, add 7.74g (69.0mmol) potassium tert.-butoxide to 2.97g (6.90mmol) from solution in methyl alcohol (83ml) of the compound of embodiment 44A.Mixture stirs and spends the night at 60 DEG C. and in order to aftertreatment, under reduced pressure remove methyl alcohol, resistates mixes with water and mixture 1N aqueous hydrochloric acid acidifying (pH1).Mixture ethyl acetate is extracted, and organic phase dried over mgso, filter and under reduced pressure concentrate.Productive rate: 2.61g (theoretical 76%, purity 84%)
LC-MS (method 5B): R t=1.02min; MS (ESIpos): m/z=417 [M+H] +.
embodiment 46A
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 300mg (0.720mmol) from the compound of embodiment 45A and 79.3mg (0.792mmol) N '-hydroxyl cyclopropane-1-carboximidamide reaction.Productive rate: 160mg (theoretical 45%)
LC-MS (method 5B): R t=1.23min; MS (ESIpos): m/z=481 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.32(s，4H)，3.92(d，1H)，3.68-3.52(m，3H)，3.44(br.s.，4H)，3.39-3.33(m，1H)，3.03-2.85(m，3H)，2.59(br.s.，5H)，2.28(d，1H)，2.16-2.06(m，1H)，1.92(q，1H)，1.10-1.01(m，2H)，0.92-0.85(m，2H)。
embodiment 47A
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 300mg (0.720mmol) from the compound of embodiment 45A and the reaction of 93.6mg (0.792mmol) N '-hydroxy-3-methoxy third amidine.Productive rate: 231mg (theoretical 63%, about 15% trans-isomer(ide))
LC-MS (method 5B): R t=1.14min; MS (ESIpos): m/z=499 [M+H] +.
embodiment 48A
The bromo-4-of 1-(1,1-bis-fluoro ethyl) benzene
The solution of 10.0g (50.2mmol) 4-bromoacetophenone in tetrahydrofuran (THF) (20ml) and 50.0ml (151mmol, in tetrahydrofuran (THF) 50%) two (2-methoxy ethyl) amino sulfur trifluoride (Deoxofluor) and 3 methanol mixed, and then stir 4 days under reflux.Then the mixture neutralization that reaction mixture is added drop-wise to saturated sodium bicarbonate aqueous solution and ice (1: 1) carefully uses ether extraction.Organic phase, by dried over sodium sulfate, is filtered and under reduced pressure concentrates.Resistates purifies (silica gel, sherwood oil/methylene dichloride 3: 1) by column chromatography.Productive rate: 8.46g (theoretical 76%)
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.52(d，2H)，1.96(t，3H)。
embodiment 49A
5-[4-(1,1-bis-fluoro ethyl) phenyl] nicotinic acid methyl ester
Under argon, under RT, 2.98g (13.3mmol) mixes from the compound of embodiment 33A and 2.03g (14.7mmol) salt of wormwood from solution in toluene (25.0ml) of the compound of embodiment 48A and the 3.62g (16.7mmol) in ethanol (8.4ml).After stirring 10min, add 1.54g (1.34mmol) tetrakis triphenylphosphine palladium and 2.33g (40.0mmol) Potassium monofluoride then in water (5.8ml).Mixture stirs 8h under reflux, cooled reaction solution and use diluted ethyl acetate.Reaction soln washs in water, and organic phase is by dried over mgso, filters and under reduced pressure concentrates.Resistates purifies (silica gel, methylene chloride/methanol 100: 1 → 80: 1) by column chromatography.Productive rate: 2.62g (theoretical 69%, 4: 1 mixtures of methyl esters and ethyl ester)
LC-MS (method 2B): R t=1.20min (methyl esters) and 1.28min (ethyl ester); MS (ESIpos): m/z=278 [M+H] +(methyl esters) and 292 [M+H] +(ethyl ester).
embodiment 50A
5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
2.30g (8.30mmol) to mix with 1.05g palladium/carbon (10% palladium) and 1.92g platinum oxide (IV) from solution in methyl alcohol (52ml) and dense hydrogen chloride solution (6.5ml) of the compound of embodiment 49A and then hydrogenated over night under standard pressure under a hydrogen atmosphere.Reaction soln is by diatomite filtration, and filter residue methanol/water is washed and the filtrate merged under reduced pressure concentrates.Resistates absorbs and then washs with 1N aqueous sodium carbonate in methylene dichloride.Organic phase, by dried over sodium sulfate, is filtered and under reduced pressure concentrates.Productive rate: 2.30g (theoretical 81%, purity 82%)
LC-MS (method 2B): R t=0.80 and 0.81min (cis/trans isomer); MS (ESIpos): m/z=284 [M+H] +.
embodiment 51A
5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidines-1,3-dicarboxylic acid 3-methyl isophthalic acid-(4-oil of mirbane) ester [the cis/trans isomer mixture of racemization]
1.30g (3.78mmol, purity 82%) mix from solution in methylene dichloride (44ml) of the compound of embodiment 50A and 1.84ml (1.34g, 13.2mmol) triethylamine and then mix with 762mg (3.78mmol) chloroformic acid 4-nitro phenyl ester at 0 DEG C.Mixture is warmed to RT and stirs 2 days.Reaction soln saturated sodium bicarbonate aqueous solution and water washing, and organic phase is by dried over mgso, filters and under reduced pressure concentrates.Productive rate: 1.93g (theoretical 92%, purity 81%, 2: 1 mixtures of methyl esters and ethyl ester)
LC-MS (Method 5B): R t=2.58min and 2.61 (methyl esters, cis/trans isomer) and 2.68and 2.70 (ethyl ester, cis/trans isomer); MS (ESIpos): m/z=278 [M+H] +(methyl esters) and 292 [M+H] +(ethyl ester).
embodiment 52A
5-[4-(1,1-bis-fluoro ethyl) phenyl]-1-(thiomorpholine-4-base carbonyl) piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
1.94g (3.50mmol, purity 81%) from solution in 1-Methyl-2-Pyrrolidone (18ml) of the compound of embodiment 51A and 1.99ml (2.17g, 21.0mmol) thiomorpholine and 1.83ml (1.36g, 10.5mmol) DIPEA mixing and be then divided into 3 parts heat 45min at 150 DEG C in single mold microwave device (Emrys Optimizer).In order to aftertreatment, merge reaction soln and directly purified by preparative HPLC.Productive rate: 530mg (theoretical 34%)
LC-MS (method 5B): R t=2.28 and 2.35min (cis/trans isomer); MS (ESIpos): m/z=413 [M+H] +.
embodiment 53A
5-[4-(1,1-bis-fluoro ethyl) phenyl]-1-(thiomorpholine-4-base carbonyl) piperidines-3-carboxylic acid [the cis/trans isomer mixture of racemization]
Under RT, add 1.44g (12.8mmol) potassium tert.-butoxide to 528mg (1.28mmol) from solution in 15ml methyl alcohol of the compound of embodiment 52A.Mixture stirs and spends the night at 60 DEG C.In order to aftertreatment, under reduced pressure remove methyl alcohol, resistates mixes with water and mixture 1N aqueous hydrochloric acid acidifying (pH 1).Mixture ethyl acetate is extracted, and organic phase dried over mgso, filter and under reduced pressure concentrate.Productive rate: 471mg (91%, 2: 1 theoretical cis/trans isomer mixtures)
LC-MS (method 5B): R t=0.99 and 1.01min; MS (ESIpos): m/z=399 [M+H] +.
embodiment 54A
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidin-1-yl }-(thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 150mg (0.376mmol) from the compound of embodiment 53A and 41.5mg (0.414mmol) N '-hydroxyl cyclopropane-1-carboximidamide reaction.Productive rate: 77.9mg (theoretical 44%)
LC-MS (method 2B): R t=1.37min; MS (ESIpos): m/z=463 [M+H] +.
embodiment 55A
5-[4-(2-hydroxyethyl) phenyl] nicotinic acid methyl ester
According to general method 3A, 6.00g (29.8mmol) 2-(4-bromophenyl) ethanol and the reaction of 19.6g (74.6mmol) 5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-base) nicotinic acid methyl ester.Productive rate: 6.12g (theoretical 74%)
LC-MS (method 2B): R t=0.86min; MS (ESIpos): m/z=258 [M+H] +.
embodiment 56A
5-[4-(2-hydroxyethyl) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
5.40g (19.6mmol) mixes with 1.00 palladiums/carbon (10% palladium) and 1.00g platinum oxide (IV) from the solution of compound in spirit acid (124ml) of embodiment 55A.This succeeded by hydrogenation 6h under standard pressure under a hydrogen atmosphere, and then adds 1.00g palladium/carbon (10% palladium) and 1.00g platinum oxide (IV), and hydrogenated over night under standard pressure under a hydrogen atmosphere.This succeeded by Parr device under 3 bar nitrogen atmosphere hydrogenation 2h again.Reaction soln is by diatomite filtration, and filter residue methanol/water is washed and the filtrate merged under reduced pressure concentrates.Resistates repeatedly uses toluene condistillation and then drying under high vacuum.Productive rate: 6.63g (theoretical 56%, purity 44%)
LC-MS (method 2B): R t=0.36min and 0.40min (cis/trans isomer); MS (ESIpos): m/z=264 [M+H] +.
embodiment 57A
1-acetyl-5-[4-(2-hydroxyethyl) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
5.58g (9.33mmol, purity 44%) mixes from solution in methylene dichloride (80ml) of the compound of embodiment 56A and 2.60ml (1.89g, 18.7mmol) triethylamine and is then cooled to 0 DEG C.At such a temperature, drip 0.33ml (0,37g, 4.67mmol) Acetyl Chloride 98Min. and mixture and stir 2h.Add 0.13ml (0.15g, 1.86mmol) Acetyl Chloride 98Min. further and mixture stirring 1h.Subsequently, the moisture 1N salt acid elution of reaction soln, and organic phase is by dried over mgso, filters and under reduced pressure concentrates.Resistates is purified (silica gel, methylene chloride/methanol 30: 1) by column chromatography, and the crude product obtained is purified by preparative HPLC again.Productive rate: 1.17g (theoretical 41%)
LC-MS (method 5B): R t=0.72min and 0.74min (cis/trans isomer); MS (ESIpos): m/z=306 [M+H] +.
embodiment 58A
1-acetyl-5-[4-(2,2-bis-fluoro ethyl) phenyl] piperidines-3-carboxylate methyl ester [the cis/trans isomer mixture of racemization]
631mg (2.05mmol) is from solution in methylene dichloride (20.8ml) of the compound of embodiment 57A and 1.45ml (1.60g, 20.5mmol) dimethyl sulfoxide (DMSO) and 1.78ml (1.32g, 10.2mmol) N, N-Diisopropylamine mixing.Subsequently, at-20 DEG C, add 1.30g (8.18mmol) sulfur trioxide-pyridine title complex and mixture stir spend the night, it slowly warms up RT during this period.Reaction soln dchloromethane, and organic phase washed with water, by dried over mgso, filter and under reduced pressure concentrate.Crude product (778mg) to start subsequently to join in methylene dichloride (5.2ml) and mixes with 0.50ml (615mg, 3.81mmol) diethylaminosulfur trifluoride (DAST) with becoming to drip under RT.Mixture stir under RT 4h and then this reaction terminate by adding 2N aqueous sodium carbonate carefully.After being separated, organic phase, by dried over mgso, is filtered and under reduced pressure concentrates.Crude product is purified by preparative HPLC.Productive rate: 120mg (theoretical 24%, purity 61%, about 2: 1 cis/trans isomer mixtures)
LC-MS (method 2B): R t=1.07min and 1.09min (cis/trans isomer); MS (ESIpos): m/z=326 [M+H] +.
embodiment 59A
1-ethanoyl-5-[4-(2,2-bis-fluoro ethyl) phenyl] piperidines-3-carboxylic acid [cis-isomeride of racemization]
Under RT, in the solution of methyl alcohol (6.9ml), add 410mg (3.65mmol) potassium tert.-butoxide to 205mg (0.365mmol, purity 61%) from the compound of embodiment 58A.Mixture stirs and spends the night at 60 DEG C.In order to aftertreatment, under reduced pressure remove methyl alcohol, resistates mixes with water and mixture 1N aqueous hydrochloric acid acidifying (pH1).Mixture ethyl acetate is extracted, and organic phase dried over mgso, filter and under reduced pressure concentrate.Productive rate: 153mg (theoretical 67%, purity 50%)
LC-MS (method 5B): R t=1.74min; MS (ESIpos): m/z=312 [M+H] +.
embodiment 60A
1-{3-[4-(2,2-bis-fluoro ethyl) phenyl]-5-[3-(2-methoxy ethyl)-1,2,4-bis- azoles-5-base] piperidin-1-yl }-ethyl ketone [cis-isomeride of racemization]
According to general method 6A, 153mg (0.270mmol, purity 50%) from the compound of embodiment 59A and the reaction of 41.3mg (0.297mmol, purity 85%) N '-hydroxy-3-methoxy third amidine.Productive rate: 46.6mg (theoretical 32%, purity 72%)
LC-MS(Method 2B)：R t＝1.07min；MS(ESIpos)：m/z＝394[M+H] +。
embodiment 61A
3-[4-(2,2-bis-fluoro ethyl) phenyl]-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidines [cis-isomeride of racemization]
45.0g (0.083mmol, purity 72%) mixes from solution in ethanol (10.0ml) of the compound of embodiment 60A and 69 μ l (15mg, 0.42mmol) concentrated hydrochloric acids.Subsequently, mixture stirs 24h under reflux, and reaction soln dilute with water use washed with diethylether.Alkalize containing aqueous phase and use dichloromethane extraction.Organic phase, by dried over mgso, is filtered and under reduced pressure concentrates.Productive rate: 36.3mg (theoretical 87%, purity 70%)
LC-MS (method 5B): R t=0.71min; MS (ESIpos): m/z=352 [M+H] +.
embodiment 62A
3-[4-(2,2-bis-fluoro ethyl) phenyl]-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidines-1-carboxylic acid 4-nitro phenyl ester [cis-isomeride of racemization]
36.3mg (0.061mmol, purity 70%) mix from solution in methylene dichloride (2.0ml) of the compound of embodiment 61A and 0.03ml (21.6mg, 0.21mmol) triethylamine and then under RT, add 12.3mg (0.061mmol) chloroformic acid 4-nitro phenyl ester.Mixture stirs 2h and then reaction soln saturated sodium bicarbonate aqueous solution and water washing under RT, and organic phase is by dried over mgso, filters and under reduced pressure concentrates.Productive rate: 56.2mg (theoretical 91%, purity 60%)
LC-MS (method 4B): R t=2.56min; MS (ESIpos): m/z=517 [M+H] +.
embodiment 63A
{ 3-[4-(2,2-bis-fluoro ethyl) phenyl]-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization]
56.0mg (0.065mmol, purity 60%) from solution in 1-Methyl-2-Pyrrolidone (2.0ml) of the compound of embodiment 62A and 37.0 μ l (40.0mg, 0.390mmol) thiomorpholine and 34.0 μ l (25.0mg, 0.195mmol) DIPEA mixes and then in single mold microwave device (Emrys Optimizer), heats 30min at 150 DEG C.In order to aftertreatment, merge reaction soln and directly to be purified by preparative HPLC.Productive rate: 14.7mg (theoretical 47%)
LC-MS (method 5B): R t=1.09min; MS (ESIpos): m/z=481 [M+H] +.
embodiment 64A
N '-hydroxyl-1-methoxy cyclopropane-1-carboximidamide
100mg (1.03mmol) 1-methoxy basic ring propionic acid amide [L.N.Owen in tetrahydrofuran (THF) (22.7ml), H.M.Babatunde Somade, J.Chem.Soc.1947,1030-1034] to mix with 1.51g (6.08mmol) N-(triethyl ammonium sulphonyl) Urethylane (burgess reagent) and then at 60 DEG C, to stir 1.5h.Reaction mixture mixes with methylene dichloride and water, and organic phase is by dried over mgso, filters and under reduced pressure concentrates (637mg crude product).Start to add 100mg crude product in ethanol (1.2ml), mix with 107mg (1.55mmol) hydroxylammonium chloride and 0.17ml (125mg, 1.24mg) triethylamine and then stir under reflux and spend the night.Reaction soln under reduced pressure concentrates, and resistates mixes with saturated sodium chloride aqueous solution and then uses dichloromethane extraction.Organic phase, by dried over mgso, is filtered and under reduced pressure concentrates.Resistates stirs by ethyl acetate subsequently, filters insoluble salt and under reduced pressure concentrated filtrate.Productive rate: 32.3mg (theoretical 23%)
1H NMR(400MHz，DMSO-d 6)：δ＝9.09(br.s.，1H)，5.39(br.s.，2H)，3.15(s，3H)，0.81(d，4H)。
embodiment 65A
{ 3-[3-(1-mcthoxycyclopropyl)-1,2,4- diazole-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization]
According to general method 6A, 93.1mg (0.224mmol) from the compound of embodiment 45A and 32.0mg (0.246mmol) N '-hydroxyl-1-methoxy cyclopropane-1-carboximidamide reaction from embodiment 64A.Productive rate: 31.1mg (theoretical 27%)
LC-MS (method 5B): R t=1.22min; MS (ESIpos): m/z=511 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝7.33(s，4H)，3.94(d，1H)，3.69-3.52(m，3H)，3.48-3.42(m，4H)，3.41-3.34(m，4H)，3.06-2.85(m，3H)，2.63-2.57(m，4H)，2.32-2.25(m，1H)，2.02-1.88(m，1H)，1.34-1.28(m，2H)，1.19-1.11(m，2H)。
embodiment 66A
Thiomorpholine-4-carboxylic acid 4-nitro phenyl ester 1,1-dioxide
Start in 100ml methylene dichloride, add 17.0g (99.2mmol) thiomorpholine 1,1-dioxide. HCl and, with being cooled with an ice bath, mix with 20.7ml (15.1g, 148.8mmol) triethylamine.Add 10.0g (49.6mmol) chloroformic acid 4-nitro phenyl ester in batches.Reaction mixture stirs 30 minutes under RT, mixes and then filter with water and ethyl acetate.Resistates is dry under high vacuum.Productive rate: 12.4g (theoretical 83%)
LC-MS (method 5B): R t=0.75min; MS (ESIpos): m/z=301 [M+H] +.
1H NMR(400MHz，DMSO-d 6)：δ＝8.34-8.28(m，2H)，7.55-7.50(m，2H)，4.01(br.s.，2H)，3.87(br.s.，2H)，3.37(br.s.，2H)，3.28(br.s.，2H)。
operation embodiment
General method 1: sulfoxide is formed
Under RT, the solution of suitable thioether (1.0 equivalent) in methylene dichloride (about 20-40ml/mmol) mixes with 50% m-chloroperoxybenzoic acid (0.9-1.0 equivalent).Reaction mixture at room temperature stirs 30min.Under reduced pressure except desolventizing and resistates are purified by preparative HPLC.
General method 2: sulfone is formed
Under RT, the solution of suitable thioether (1.0 equivalent) in methylene dichloride (about 20-40ml/mmol) mixes with 50% m-chloroperoxybenzoic acid (2.5 equivalent).Reaction mixture at room temperature stirs 30min.Under reduced pressure except desolventizing and resistates are purified by preparative HPLC.
embodiment 1
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl }-(oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,100mg (0.200mmol) from embodiment 26A.Productive rate: 90mg (theoretical 87%)
LC-MS (method 5B): R t=0.97min; MS (ESIpos): m/z=517 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.48(d，2H)，7.33(d，3H)，3.99(d，1H)，3.69-3.66(m，3H)，3.65-3.58(m，4H)，3.57-3.48(m，3H)，3.23(s，3H)，3.09-2.88(m，7H)，2.75-2.66(m，3H)，2.35-2.28(m，1H)，2.00(m，1H)。
embodiment 2
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl }-(1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,100mg (0.207mmol) from embodiment 27A.Productive rate: 95mg (theoretical 91%)
LC-MS (method 5B): R t=1.05min; MS (ESIpos): m/z=499 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.47(d，2H)，7.33(d，2H)，3.95(d，1H)，3.67-3.48(m，5H)，3.05-2.85(m，5H)，2.75-2.65(m，2H)，2.28(d，1H)，2.14-2.08(m，1H)，1.94(q，1H)，1.09-1.01(m，2H)，0.92-0.84(m，2H)。
embodiment 3
[3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-(4-ethylphenyl) piperidin-1-yl] (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,55mg (0.130mmol) from embodiment 9A.Productive rate: 43mg (theoretical 75%)
LC-MS (method 5B): R t=1.06min; MS (ESIpos): m/z=443 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.24(d，2H)，7.17(d，2H)，3.96(d，2H)，3.67-3.46(m，5H)，3.045-2.85(m，5H)，2.74-2.66(m，2H)，2.57(q，2H)，2.25(d，1H)，2.14-2.06(m，1H)，1.91(q，1H)，1.16(t，3H)，1.08-1.02(m，2H)，0.91-0.86(m，2H)。
embodiment 4
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-(4-ethylphenyl) piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,50mg (0.109mmol) from embodiment 11A.Productive rate: 17mg (theoretical 32%)
LC-MS (method 5B): R t=1.01min; MS (ESIpos): m/z=475 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.23(d，2H)，7.17(d，2H)，3.98(d，2H)，3.71(t，2H)，3.67-3.47(m，4H)，3.43(q，1H)，3.07-2.89(m，3H)，2.75-2.66(m，3H)，2.57(q，3H)，1.95(q，1H)，1.24(br s，1H)，1.16(t， 3H)，1.07(t，3H)。
embodiment 5
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-(4-ethylphenyl) piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
According to method 6D, the stage enantiomer separation from the racemic mixture of embodiment 4 produces 37.7mg from the title compound of embodiment 5 and the 20.0mg title compound from embodiment 6.
LC-MS (method 5B): R t=1.01min; MS (ESIpos): m/z=475 [M+H] +;
HPLC (method 1E): R t=6.48min, > 99.5%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.23(d，2H)，7.17(d，2H)，3.98(d，2H)，3.71(t，2H)，3.67-3.47(m，4H)，3.43(q，1H)，3.07-2.89(m，3H)，2.75-2.66(m，3H)，2.57(q，3H)，1.95(q，1H)，1.24(br s，1H)，1.16(t，3H)，1.07(t，3H)。
embodiment 6
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-(4-ethylphenyl) piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
According to method 6D, the stage enantiomer separation from the racemic mixture of embodiment 4 produces 37.7mg from the title compound of embodiment 5 and the 20.0mg title compound from embodiment 6.
LC-MS (method 5B): R t=1.01min; MS (ESIpos): m/z=475 [M+H] +;
HPLC (method 1E): R t=7.27min, > 99.5%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.23(d，2H)，7.17(d，2H)，3.98(d，2H)，3.71(t，2H)，3.67-3.47(m，4H)，3.43(q，1H)，3.07-2.89(m，3H)，2.75-2.66(m，3H)，2.57(q，3H)，1.95(q，1H)，1.24(br s，1H)，1.16(t，3H)，1.07(t，3H)。
embodiment 7
{ 3-[3-(2-hydroxyethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,80mg (0.170mmol) from embodiment 20A.Productive rate: 77mg (theoretical 91%)
LC-MS (method 5B): R t=0.85min; MS (ESIpos): m/z=487 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.58(d，2H)，4.77(t，1H)，3.99(d，1H)，3.74(q，2H)，3.68-3.59(m，3H)，3.57-3.48(m，2H)，3.48-3.38(m，1H)，3.12-3.01(m，3H)，2.98-2.86(m 2H)，2.85-2.80(m，2H)，1.55(q，1H)。
embodiment 8
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-methoxy ethyl)-1,2,4- azoles-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,150mg (0.300mmol) from embodiment 26A.65.0mg is produced from the title compound of embodiment 8 and the 72.0mg title compound from embodiment 9 according to the stage enantiomer separation of method 1D racemic mixture.
LC-MS (method 5B): R t=1.04min; MS (ESIpos): m/z=533 [M+H] +;
HPLC (method 2E): R t=15.64min, > 99.5%ee;
1H NMR (400MHz，DMSO-d 6)：δ＝7.48(d，2H)，7.33(d，2H)，4.03(d，1H)，3.70-3.58(m，7H)，3.45-3.35(m，1H)，3.23(s，3H)，3.21-3.15(m，4H)，3.12-2.90(m，5H)，2.33(d，1H)，1.97(q，1H)。
embodiment 9
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-methoxy ethyl)-1,2,4-bis- azoles-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,150mg (0.300mmol) from embodiment 26A.65.0mg is produced from the title compound of embodiment 8 and the 72.0mg title compound from embodiment 9 according to the stage enantiomer separation of method 1D racemic mixture.
LC-MS (method 5B): R t=1.04min; MS (ESIpos): m/z=533 [M+H] +;
HPLC (method 2E): R t=42.42min, > 99.5%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.48(d，2H)，7.33(d，2H)，4.03(d，1H)，3.70-3.58(m，7H)，3.45-3.35(m，1H)，3.23(s，3H)，3.21-3.15(m，4H)，3.12-2.90(m，5H)，2.33(d，1H)，1.97(q，1H)。
embodiment 10
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
under RT, 136mg (0.281mmol) { 3-(the 3-cyclopropyl-1,2,4-in methylene dichloride (11.6ml) diazole-5-base)-5-[4-(trifluoromethoxy) phenyl]-piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization] (embodiment 27A) mix with 243mg (0.703mmol) m-chloroperoxybenzoic acid and then stir 30min.Reaction soln under reduced pressure concentrates, and resistates is absorbed and purified by preparative HPLC in acetonitrile.61.7mg is produced from the title compound of embodiment 10 and the 59.6mg title compound from embodiment 11 according to the stage enantiomer separation of method 2D 136mg racemic mixture.
LC-MS (method 5B): R t=1.12min; MS (ESIpos): m/z=515 [M+H] +;
HPLC (method 3E): R t=4.26min, > 99.05%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.47(d，2H)，7.33(d，2H)，3.99(d，1H)，3.67-3.56(m，5H)，3.40-3.33(m，1H)，3.20-3.14(m，4H)，3.08-2.96(m，3H)，2.28(d，1H)，2.14-2.06(m，1H)，1.94(q，1H)，1.08-1.03(m，2H)，0.91-0.86(m，2H)。
embodiment 11
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
Under RT, 136mg (0.281mmol) { 3-(the 3-cyclopropyl-1,2,4-in methylene dichloride (11.6ml) diazole-5-base)-5-[4-(trifluoromethoxy) phenyl]-piperidin-1-yl } (thiomorpholine-4-base) ketone [cis-isomeride of racemization] (embodiment 27A) mix with 243mg (0.703mmol) m-chloroperoxybenzoic acid and then stir 30min.Reaction soln under reduced pressure concentrates, and resistates is absorbed and purified by preparative HPLC in acetonitrile.61.7mg is produced from the title compound of embodiment 10 and the 59.6mg title compound from embodiment 11 according to the stage enantiomer separation of method 2D 136mg racemic mixture.
LC-MS (method 5B): R t=1.12min; MS (ESIpos): m/z=515 [M+H] +;
HPLC (method 3E): R t=5.68min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.47(d，2H)，7.33(d，2H)，3.99(d，1H)，3.67-3.56(m，5H)，3.40-3.33(m，1H)，3.20-3.14(m，4H)，3.08-2.96(m，3H)，2.28(d，1H)，2.14-2.06(m，1H)，1.94(q，1H)，1.08-1.03(m，2H)，0.91-0.86(m，2H)。
embodiment 12
(1,1-dioxothiomorpholin-4-base) { 3-(4-ethylphenyl)-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,77.0mg (0.173mmol) from embodiment 8A.36.0mg is produced from the title compound of embodiment 12 and the 35.0mg title compound from embodiment 13 according to the stage enantiomer separation of method 3D 74.9mg racemic mixture.
LC-MS (method 2B): R t=1.17min; MS (ESIpos): m/z=477 [M+H] +;
HPLC (method 4E): R t=5.49min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.23(d，2H)，7.17(d，2H)，4.03(d，1H)，3.73-3.56(m，7H)，3.46-3.35(m，1H)，3.23(s，3H)，3.17(br s，4H)，3.06(t，1H)，3.01-2.83(m，4H)，2.58(d，3H)，2.30(d，1H)，1.95(q，1H)，1.16(t，3H)。
embodiment 13
(1,1-dioxothiomorpholin-4-base) { 3-(4-ethylphenyl)-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,77.0mg (0.173mmol) from embodiment 8A.36.0mg is produced from the title compound of embodiment 12 and the 35.0mg title compound from embodiment 13 according to the stage enantiomer separation of method 3D 74.9mg racemic mixture.
LC-MS (method 2B): R t=1.17min; MS (ESIpos): m/z=477 [M+H] +;
HPLC (method 4E): R t=12.07min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.23(d，2H)，7.17(d，2H)，4.03(d，1H)，3.73-3.56(m，7H)，3.46-3.35(m，1H)，3.23(s，3H)，3.17(br s，4H)，3.06(t，1H)，3.01-2.83(m，4H)，2.58(d，3H)，2.30(d，1H)，1.95(q，1H)，1.16(t，3H)。
embodiment 14
[3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-(4-ethylphenyl) piperidin-1-yl] (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,55mg (0.130mmol) from embodiment 9A.23.0mg is produced from the title compound of embodiment 14 and the 23.0mg title compound from embodiment 15 according to the stage enantiomer separation of method 4D 53.3mg racemic mixture.
LC-MS (method 2B): R t=1.30min; MS (ESIpos): m/z=459 [M+H] +;
HPLC (method 5E): R t=8.89min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.23(d，2H)，7.16(d，2H)，3.99(d，1H)，3.67-3.55(m，5H)，3.39-3.32(m，1H)，3.17(br s，4H)，3.07-2.91(m，2H)，2.91-2.81(m，1H)，2.62-2.55(m，2H)，2.26(d，1H)，2.16-2.08(m，1H)，1.91(q，1H)，1.16(t，3H)，1.10-1.02(m，2H)，0.92-0.85(m，2H)。
embodiment 15
[3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-(4-ethylphenyl) piperidin-1-yl] (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,55.5mg (0.130mmol) from embodiment 9A.23.0mg is produced from the title compound of embodiment 14 and the 23.0mg title compound from embodiment 15 according to the stage enantiomer separation of method 4D 53.3mg racemic mixture.
LC-MS (method 2B): R t=1.27min; MS (ESIpos): m/z=459 [M+H] +;
HPLC (method 5E): R t=12.06min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.23(d，2H)，7.16(d，2H)，3.99(d，1H)，3.67-3.55(m，5H)，3.39-3.32(m，1H)，3.17(br s，4H)，3.07-2.91(m，2H)，2.91-2.81(m，1H)，2.62-2.55(m，2H)，2.26(d，1H)，2.16-2.08(m，1H)，1.91(q，1H)，1.16(t，3H)，1.10-1.02(m，2H)，0.92-0.85(m，2H)。
embodiment 16
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,269mg (0.578mmol) from embodiment 17A.57.8mg is produced from the title compound of embodiment 16 and the 99.7mg title compound from embodiment 17 according to the stage enantiomer separation of method 1D 292mg racemic mixture.
LC-MS (method 2B): R t=1.26min; MS (ESIpos): m/z=499 [M+H] +;
HPLC (method 1E): R t=10.53min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.57(d，2H)，4.00(d，1H)，3.67(d，1H)，3.61(br s，4H)，3.44-3.33(m，1H)，3.17(br s，4H)，3.12-2.98(m，3H)，2.31(d，1H)，2.11(dt，1H)，1.98(q，1H)，1.12-1.00(m，2H)，0.95-0.84(m，2H)。
embodiment 17
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,269mg (0.578mmol) from embodiment 17A.57.8mg is produced from the title compound of embodiment 16 and the 99.7mg title compound from embodiment 17 according to the stage enantiomer separation of method 1D 292mg racemic mixture.
LC-MS (method 2B): R t=1.26min; MS (ESIpos): m/z=499 [M+H] +;
HPLC (method 1E): R t=16.04min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.57(d，2H)，4.00(d，1H)，3.67(d，1H)，3.61(br s，4H)，3.44-3.33(m，1H)，3.17(br s，4H)，3.12-2.98(m，3H)，2.31(d，1H)，2.11(dt，1H)，1.98(q，1H)，1.12-1.00(m，2H)，0.95-0.84(m，2H)。
embodiment 18
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-ethoxyethyl group)-1,2,4-bis- azoles-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,317mg (0.616mmol) from embodiment 28A.132mg is produced from the title compound of embodiment 18 and the 129mg title compound from embodiment 19 according to the stage enantiomer separation of method 2D 294mg racemic mixture.
LC-MS (method 6B): R t=2.34min; MS (ESIpos): m/z=547 [M+H] +;
HPLC (method 3E): R t=4.60min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.48(d，2H)，7.33(d，2H)，4.03(d，1H)，3.71(t，2H)，3.68-3.56(m，5H)，3.43(q，3H)，3.17(br s，4H)，3.07(t，1H)，3.01(d，2H)，2.93(t，2H)，2.32(d，1H)，2.05-1.91(m，1H)，1.07(t，3H)。
embodiment 19
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-ethoxyethyl group)-1,2,4-bis- azoles-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,317mg (0.616mmol) from embodiment 28A.132mg is produced from the title compound of embodiment 18 and the 129mg title compound from embodiment 19 according to the stage enantiomer separation of method 2D 294mg racemic mixture.
LC-MS (method 6B): R t=2.34min; MS (ESIpos): m/z=547 [M+H] +;
HPLC (method 3E): R t=11.53min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.48(d，2H)，7.33(d，2H)，4.03(d，1H)，3.71(t，2H)，3.68-3.56(m，5H)，3.43(q，3H)，3.17(br s，4H)，3.07(t，1H)，3.01(d，2H)，2.93(t，2H)，2.32(d，1H)，2.05-1.91(m，1H)，1.07(t，3H)。
embodiment 20
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1-oxo sulfo--morpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,50.0mg (0.107mmol) from embodiment 17A.Productive rate: 4.3mg (theoretical 8%)
LC-MS (method 5B): R t=1.05min; MS (ESIpos): m/z=483 [M+H] +.
embodiment 21
{ 3-[3-(2-hydroxyethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl }-(1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,100.0mg (0.206mmol) from embodiment 29A.Productive rate: 105.2mg (theoretical 99%)
LC-MS (method 5B): R t=0.89min; MS (ESIpos): m/z=503 [M+H] +.
embodiment 22
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,50.0mg (0.100mmol) from embodiment 19A.Productive rate: 50.2mg (theoretical 92%)
LC-MS (method 5B): R t=1.02min; MS (ESIpos): m/z=515 [M+H] +.
embodiment 23
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
25.5mg is produced from the title compound of embodiment 23 and the 22.4mg title compound from embodiment 24 from the stage enantiomer separation of the racemic mixture of embodiment 22 according to method 1D 50.2mg.
LC-MS (method 2B): R t=1.14min; MS (ESIpos): m/z=515 [M+H] +;
HPLC (method 2E): R t=7.51min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.58(d，2H)，4.00(d，1H)，3.71(t，2H)，3.63(d，3H)，3.57-3.48(m，2H)，3.43(q，3H)，3.14-3.00(m，3H)，2.93(t，4H)，2.77-2.65(m，2H)，2.35(d，1H)，2.10-1.95(m，1H)，1.06(m，3H)。
embodiment 24
{ 3-[3-(2-ethoxyethyl group)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
25.5mg is produced from the title compound of embodiment 23 and the 22.4mg title compound from embodiment 24 from the stage enantiomer separation of the racemic mixture of embodiment 22 according to method 1D 50.2mg.
LC-MS (method 2B): R t=1.14min; MS (ESIpos): m/z=515 [M+H] +;
HPLC (method 2E): R t=13.93min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.58(d，2H)，4.00(d，1H)，3.71(t，2H)，3.63(d，3H)，3.57-3.48(m，2H)，3.43(q，3H)，3.14-3.00(m，3H)，2.93(t，4H)，2.77-2.65(m，2H)，2.35(d，1H)，2.10-1.95(m，1H)，1.06(m，3H)。
embodiment 25
{ 3-(4-ethylphenyl)-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (1-oxo sulfo--morpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,77.0mg (0.173mmol) from embodiment 8A.Productive rate: 63.2mg (theoretical 79%)
LC-MS (method 5B): R t=0.97min; MS (ESIpos): m/z=461 [M+H] +;
1h NMR (400MHz, DMSO-d 6): δ=7.23 (m, 2H), 7.17 (m, 2H), 3.99 (d, 1H), 3.72-3.46 (m, 7H), 3.46-3.34 (m, 2H), (3.09-2.98 m, 1H), 2.97-2.83 (m, 6H), (2.65 br s, 1H), 2.76-2.64 (m, 2H), (2.58 d, 3H), 2.30 (d, 1H), (1.95 q, 1H), 1.16 (t, 3H); A hiding proton.
embodiment 26
{ 3-(4-ethylphenyl)-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (1-oxo sulfo--morpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
17.8mg is produced from the title compound of embodiment 26 and the 18.7mg title compound from embodiment 27 from the stage enantiomer separation of the racemic mixture of embodiment 25 according to method 6D 63.2mg.
LC-MS (method 5B): R t=0.97min; MS (ESIpos): m/z=461 [M+H] +;
HPLC (method 2E): R t=6.48min, > 99.0%ee;
1h NMR (400MHz, DMSO-d 6): δ=7.23 (m, 2H), 7.17 (m, 2H), 3.99 (d, 1H), 3.72-3.46 (m, 7H), 3.46-3.34 (m, 2H), (3.09-2.98 m, 1H), 2.97-2.83 (m, 6H), (2.65 br s, 1H), 2.76-2.64 (m, 2H), (2.58 d, 3H), 2.30 (d, 1H), (1.95 q, 1H), 1.16 (t, 3H); A hiding proton.
embodiment 27
{ 3-(4-ethylphenyl)-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (1-oxo sulfo--morpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
17.8mg is produced from the title compound of embodiment 26 and the 18.7mg title compound from embodiment 27 from the stage enantiomer separation of the racemic mixture of embodiment 25 according to method 6D 63.2mg.
LC-MS (method 5B): R t=0.97min; MS (ESIpos): m/z=461 [M+H] +;
HPLC (method 2E): R t=7.97min, > 99.0%ee;
1h NMR (400MHz, DMSO-d 6): δ=7.23 (m, 2H), 7.17 (m, 2H), 3.99 (d, 1H), 3.72-3.46 (m, 7H), 3.46-3.34 (m, 2H), (3.09-2.98 m, 1H), 2.97-2.83 (m, 6H), (2.65 br s, 1H), 2.76-2.64 (m, 2H), (2.58 d, 3H), 2.30 (d, 1H), (1.95 q, 1H), 1.16 (t, 3H); A hiding proton.
embodiment 28
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-methoxy ethyl)-1,2,4-bis- azoles-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,269mg (0.556mmol) from embodiment 18A.126mg is produced from the title compound of embodiment 28 and the 122mg title compound from embodiment 29 according to the stage enantiomer separation of method 5D racemic mixture.
LC-MS (method 6B): R t=2.18min; MS (ESIpos): m/z=517 [M+H] +;
HPLC (method 2E): R t=4.98min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.58(d，2H)，4.03(d，1H)，3.68(t，3H)，3.62(br s，4H)，3.49-3.38(m，1H)，3.23(s，3H)，3.18(br s，4H)，3.14-3.02(m，3H)，2.94(t，2H)，2.35(d，1H)，2.02(d，1H)。
embodiment 29
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-methoxy ethyl)-1,2,4-bis- azoles-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,269mg (0.556mmol) from embodiment 18A.126mg is produced from the title compound of embodiment 28 and the 122mg title compound from embodiment 29 according to the stage enantiomer separation of method 5D racemic mixture.
LC-MS (method 6B): R t=2.18min; MS (ESIpos): m/z=517 [M+H] +;
HPLC (method 2E): R t=15.96min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.58(d，2H)，4.03(d，1H)，3.68(t，3H)，3.62(br s，4H)，3.49-3.38(m，1H)，3.23(s，3H)，3.18(br s，4H)，3.14-3.02(m，3H)，2.94(t，2H)，2.35(d，1H)，2.02(d，1H)。
embodiment 30
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-ethoxyethyl group)-1,2,4-bis- azoles-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,259mg (0.519mmol) from embodiment 19A.104mg is produced from the title compound of embodiment 30 and the 91.0mg title compound from embodiment 31 according to the stage enantiomer separation of method 2D 252mg racemic mixture.
LC-MS (method 6B): R t=2.29min; MS (ESIpos): m/z=531 [M+H] +;
HPLC (method 3E): R t=4.92min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.71(d，2H)，7.58(d，2H)，4.03(d，1H)，3.75-3.68(m，3H)，3.62(br s，4H)，3.43(q，3H)，3.18(br s，4H)，3.14-3.01(m，3H)，2.93(t，2H)，2.35(d，1H)，2.12-1.95(m，1H)，1.07(t，3H)。
embodiment 31
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-ethoxyethyl group)-1,2,4-bis- azoles-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,259mg (0.519mmol) from embodiment 19A.104mg is produced from the title compound of embodiment 30 and the 91.0mg title compound from embodiment 31 according to the stage enantiomer separation of method 2D 252mg racemic mixture.
LC-MS (method 6B): R t=2.29min; MS (ESIpos): m/z=531 [M+H] +;
HPLC (method 3E): R t=13.63min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.71(d，2H)，7.58(d，2H)，4.03(d，1H)，3.75-3.68(m，3H)，3.62(br s，4H)，3.43(q，3H)，3.18(br s，4H)，3.14-3.01(m，3H)，2.93(t，2H)，2.35(d，1H)，2.12-1.95(m，1H)，1.07(t，3H)。
embodiment 32
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-hydroxyethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,100mg (0.213mmol) from embodiment 20A.33.9mg is produced from the title compound of embodiment 32 and the 35.0mg title compound from embodiment 33 according to the stage enantiomer separation of method 2D 97.4mg racemic mixture.
LC-MS (method 5B): R t=0.91min; MS (ESIpos): m/z=503 [M+H] +;
HPLC (method 3E): R t=4.75min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.71(d，2H)，7.58(d，2H)，4.77(t，1H)，4.03(d，1H)，3.74(q，2H)，3.68(d，1H)，3.62(br s，4H)，3.47-3.37(m，1H)，3.18(br s，4H)，3.13-3.00(m，3H)，2.82(t，2-H)，2.35(d，1H)，2.10-1.94(m，1H)。
embodiment 33
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-hydroxyethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,100mg (0.213mmol) from embodiment 20A.33.9mg is produced from the title compound of embodiment 32 and the 35.0mg title compound from embodiment 33 according to the stage enantiomer separation of method 2D 97.4mg racemic mixture.
LC-MS (method 5B): R t=0.91min; MS (ESIpos): m/z=503 [M+H] +;
HPLC (method 3E): R t=8.97min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.71(d，2H)，7.58(d，2H)，4.77(t，1H)，4.03(d，1H)，3.74(q，2H)，3.68(d，1H)，3.62(br s，4H)，3.47-3.37(m，1H)，3.18(br s，4H)，3.13-3.00(m，3H)，2.82(t，2-H)，2.35(d，1H)，2.10-1.94(m，1H)。
embodiment 34
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-ethoxyethyl group)-1,2,4-bis- azoles-5-base]-5-(4-ethylphenyl)-piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,303mg (0.661mmol) from embodiment 11A.139mg is produced from the title compound of embodiment 34 and the 117mg title compound from embodiment 35 according to the stage enantiomer separation of method 2D 297mg racemic mixture.
LC-MS (method 2B): R t=1.24min; MS (ESIpos): m/z=491 [M+H] +;
HPLC (method 3E): R t=4.81min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.24(m，2H)，7.17(m，2H)，4.03(d，1H)，3.71(t，2H)，3.67-3.57(m，5H)，3.49-3.35(m，3H)，3.17(br s，4H)，3.06(t，1H)，2.98-2.86(m，3H)，2.62-2.55(m，3H)，2.30(d，2H)，1.95(q，1H)，1.16(t，3H)，1.07(t，3H)。
embodiment 35
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-ethoxyethyl group)-1,2,4-bis- azoles-5-base]-5-(4-ethylphenyl)-piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React according to the compound of general method 2,303mg (0.661mmol) from embodiment 11A.139mg is produced from the title compound of embodiment 34 and the 117mg title compound from embodiment 35 according to the stage enantiomer separation of method 2D 297mg racemic mixture.
LC-MS (method 2B): R t=1.24min; MS (ESIpos): m/z=491 [M+H] +;
HPLC (method 3E): R t=6.80min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.24(m，2H)，7.17(m，2H)，4.03(d，1H)，3.71(t，2H)，3.67-3.57(m，5H)，3.49-3.35(m，3H)，3.17(br s，4H)，3.06(t，1H)，2.98-2.86(m，3H)，2.62-2.55(m，3H)，2.30(d，2H)，1.95(q，1H)，1.16(t，3H)，1.07(t，3H)。
embodiment 36
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React according to the compound of general method 1,196mg (0.405mmol) from embodiment 18A.Productive rate: 194mg (theoretical 96%)
LC-MS (method 2B): R t=1.08min; MS (ESIpos): m/z=501 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.58(d，2H)，4.00(d，1H)，3.73-3.58(m，5H)，3.57-3.48(m，2H)，3.48-3.39(m，1H)，3.13-2.99(m，3H)，2.97-2.84(m，4H)，2.77-2.65(m，2H)，2.35(d，1H)，2.03(q，1H)。
embodiment 37
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
81.1mg is produced from the title compound of embodiment 37 and the 78.5mg title compound from embodiment 38 from the stage enantiomer separation of the racemic mixture of embodiment 36 according to method 1D 194mg.
LC-MS (method 2B): R t=1.08min; MS (ESIpos): m/z=501 [M+H] +;
HPLC (method 1E): R t=8.45min, > 99.0%ee;
1H NMR(，400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.58(d，2H)，4.00(d，1H)，3.73-3.58(m，5H)，3.57-3.48(m，2H)，3.48-3.39(m，1H)，3.13-2.99(m，3H)，2.97-2.84(m，4H)，2.77-2.65(m，2H)，2.35(d，1H)，2.03(q，1H)。
embodiment 38
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(trifluoromethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
81.1mg is produced from the title compound of embodiment 37 and the 78.5mg title compound from embodiment 38 from the stage enantiomer separation of the racemic mixture of embodiment 36 according to method 1D 194mg.
LC-MS (method 2B): R t=1.08min; MS (ESIpos): m/z=501 [M+H] +;
HPLC (method 1E): R t=18.94min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.70(d，2H)，7.58(d，2H)，4.00(d，1H)，3.73-3.58(m，5H)，3.57-3.48(m，2H)，3.48-3.39(m，1H)，3.13-2.99(m，3H)，2.97-2.84(m，4H)，2.77-2.65(m，2H)，2.35(d，1H)，2.03(q，1H)。
embodiment 39
{ 3-[4-(2,2-bis-fluoro ethyl) phenyl]-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of racemization]
React from the compound of embodiment 63A and 26.3mg (0.076mmol) m-chloroperoxybenzoic acid according to general method 2,14.7mg (0.031mmol).Productive rate: 9.5mg (theoretical 60%)
1H NMR(400MHz，DMSO-d 6)：δ＝7.33(d，2H)，7.26(m，2H)，6.23(tt，1H)，4.03(d，1H)，3.71-3.56(m，7H)，3.46-3.36(m，1H)，3.23(s，3H)，3.21-3.13(m，5H)，3.12-2.87(m，6H)，2.31(d，1H)，1.97(q，1H)。
embodiment 40
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React from the compound of embodiment 46A and 50.4mg (0.146mmol) m-chloroperoxybenzoic acid according to general method 1,78.0mg (0.162mmol).Productive rate: 76.2mg (theoretical 88%)
LC-MS (method 5B): R t=1.02min; MS (ESIpos): m/z=497 [M+H] +.
embodiment 41
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
29.1mg is produced from the title compound (enantiomer 1) of embodiment 41 and the 28.9mg title compound (enantiomer 2) from embodiment 42 from the stage enantiomer separation of the racemic mixture of embodiment 40 according to method 7D 76.2mg.
LC-MS (method 7B): R t=2.18min; MS (ESIpos): m/z=497 [M+H] +;
HPLC (method 6E): R t=13.2min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.37-7.29(m，4H)，3.96(d，1H)，3.68-3.47(m，7H)，3.41-3.33(m，1H)，3.07-2.85(m，5H)，2.74-2.66(m，2H)，2.28(d，1H)，2.16-2.08(m，1H)，1.93(q，1H)，1.08-1.02(m，2H)， 0.92-0.85(m，2H)。
embodiment 42
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
29.1mg is produced from the title compound (enantiomer 1) of embodiment 41 and the 28.9mg title compound (enantiomer 2) from embodiment 42 from the stage enantiomer separation of the racemic mixture of embodiment 40 according to method 7D 76.2mg.
LC-MS (method 7B): R t=2.18min; MS (ESIpos): m/z=497 [M+H] +;
HPLC (method 6E): R t=16.4min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.37-7.29(m，4H)，3.96(d，1H)，3.68-3.47(m，7H)，3.41-3.33(m，1H)，3.07-2.85(m，5H)，2.74-2.66(m，2H)，2.28(d，1H)，2.16-2.08(m，1H)，1.93(q，1H)，1.08-1.02(m，2H)，0.92-0.85(m，2H)。
embodiment 43
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of racemization]
React from the compound of embodiment 46A and 140mg (0.146mmol) m-chloroperoxybenzoic acid according to general method 2,78.0mg (0.162mmol).Productive rate: 87.5mg (theoretical 100%)
LC-MS (method 2B): R t=1.25min; MS (ESIpos): m/z=513 [M+H] +.
embodiment 44
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
29.1mg is produced from the title compound (enantiomer 1) of embodiment 44 and the 30.7mg title compound (enantiomer 2) from embodiment 45 from the stage enantiomer separation of the racemic mixture of embodiment 43 according to method 8D 87.5mg.
LC-MS (method 7B): R t=2.34min; MS (ESIpos): m/z=513 [M+H] +;
HPLC (method 7E): R t=9.86min, 99.0%ee;
1h NMR (400MHz, DMSO-d 6): δ=7.37-7.29 (m, 4H), 4.00 (d, 1H), (3.67-3.56 m, 7H), 3.17 (br.s., 4H), (3.07-2.87 m, 3H), 2.28 (d, 1H), 2.16-2.08 (m, 1H), 1.93 (q, 1H), 1.09-1.02 (m, 2H), 0.92-0.85 (m, 3H), a hiding proton.
embodiment 45
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
29.1mg is produced from the title compound (enantiomer 1) of embodiment 44 and the 30.7mg title compound (enantiomer 2) from embodiment 45 from the stage enantiomer separation of the racemic mixture of embodiment 43 according to method 8D 87.5mg.
LC-MS (method 7B): R t=2.34min; MS (ESIpos): m/z=513 [M+H] +;
HPLC (method 7E): R t=10.9min, 97.5%ee;
1h NMR (400MHz, DMSO-d 6): δ=7.37-7.29 (m, 4H), 4.00 (d, 1H), (3.67-3.56 m, 7H), 3.17 (br.s., 4H), (3.07-2.87 m, 3H), 2.28 (d, 1H), 2.16-2.08 (m, 1H), 1.93 (q, 1H), 1.09-1.02 (m, 2H), 0.92-0.85 (m, 3H), a hiding proton.
embodiment 46
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
React with 70.4mg (0.204mmol) m-chloroperoxybenzoic acid according to the compound reaction of general method 1,113mg (0.227mmo1) from embodiment 47A.37.1mg is produced from the title compound (enantiomer 1) of embodiment 46 and the 41.8mg title compound (enantiomer 2) from embodiment 47 according to the stage enantiomer separation of method 9D 108mg racemic mixture.
LC-MS (method 5B): R t=0.96min; MS (ESIpos): m/z=515 [M+H] +;
HPLC (method 8E): R t=5.48min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.38-7.29(m，4H)，4.00(d，1H)，3.72-3.48(m，9H)，3.46-3.37(m，1H)，3.23(s，3H)，3.10-2.85(m，7H)，2.76-2.65(m，3H)，2.32(d，1H)，1.98(q，1H)。
embodiment 47
{ 3-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
React with 70.4mg (0.204mmol) m-chloroperoxybenzoic acid according to the compound reaction of general method 1,113mg (0.227mmol) from embodiment 47A.37.1mg is produced from the title compound (enantiomer 1) of embodiment 46 and the 41.8mg title compound (enantiomer 2) from embodiment 47 according to the stage enantiomer separation of method 9D 108mg racemic mixture.
LC-MS (method 5B): R t=0.96min; MS (ESIpos): m/z=515 [M+H] +;
HPLC (method 8E): R t=7.15min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.38-7.29(m，4H)，4.00(d，1H)，3.72-3.48(m，9H)，3.46-3.37(m，1H)，3.23(s，3H)，3.10-2.85(m，7H)，2.76-2.65(m，3H)，2.32(d，1H)，1.98(q，1H)。
embodiment 48
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-methoxy ethyl)-1,2,4-bis- azoles-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React with 196mg (0.567mmol) m-chloroperoxybenzoic acid according to the compound reaction of general method 2,113mg (0.227mmol) from embodiment 47A.34.4mg is produced from the title compound (enantiomer 1) of embodiment 48 and the 29.2mg title compound (enantiomer 2) from embodiment 49 according to the stage enantiomer separation of method 9D 121mg racemic mixture.
LC-MS (method 7B): R t=2.17min; MS (ESIpos): m/z=531 [M+H] +;
HPLC (method 8E): R t=4.34min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.39-7.29(m，4H)，4.03(d，1H)，3.72-3.56(m，10H)，3.46-3，36(m，1H)，3.23(s，3H)，3.18(br.s.，4H)，3.11-2.90(m，5H)，2.33-2.27(m，1H)，1.97(q，1H)。
embodiment 49
(1,1-dioxothiomorpholin-4-base) { 3-[3-(2-methoxy ethyl)-1,2,4-bis- azoles-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
React from the compound of embodiment 47A and 196mg (0.567mmol) m-chloroperoxybenzoic acid according to general method 2,113mg (0.227mmol).34.4mg is produced from the title compound (enantiomer 1) of embodiment 48 and the 29.2mg title compound (enantiomer 2) from embodiment 49 according to the stage enantiomer separation of method 9D 121mg racemic mixture.
LC-MS (method 7B): R t=2.18min; MS (ESIpos): m/z=531 [M+H] +;
HPLC (method 8E): R t=7.86min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.39-7.29(m，4H)，4.03(d，1H)，3.72-3.56(m，10H)，3.46-3.36(m，1H)，3.23(s，3H)，3.18(br.s.，4H)，3.11-2.90(m，5H)，2.33-2.27(m，1H)，1.97(q，1H)。
embodiment 50
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidin-1-yl }-(1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
React from the compound of embodiment 54A and 22.9mg (0.066mmol) m-chloroperoxybenzoic acid according to general method 1,34.1mg (0.074mmol).Productive rate: 39.7mg (theoretical 100%).
LC-MS (method 5B): R t=0.99min; MS (ESIpos): m/z=479 [M+H] +.
embodiment 51
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidin-1-yl }-(1-oxygen-thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
12.0mg is produced from the title compound (enantiomer 1) of embodiment 51 and the 14.0mg title compound (enantiomer 2) from embodiment 52 from the stage enantiomer separation of the racemic mixture of embodiment 50 according to method 9D 35.5mg.
LC-MS (method 5B): R t=1.00min; MS (ESIpos): m/z=479 [M+H] +;
HPLC (method 9E): R t=5.27min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.53(d，2H)，7.45(d，2H)，3.96(d，1H)，3.71-3.46(m，5H)，3.42-3.35(m，1H)，3.09-2.84(m，5H)，2.71(d，2H)，2.29(d，1H)，2.16-2.08(m，1H)，2.02-1.90(m，4H)，1.10-1.02(m，2H)，0.93-0.85(m，2H)。
embodiment 52
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidin-1-yl }-(1-oxo thiomorpholine-4-base) ketone [cis-isomeride of enantiomer-pure]
12.0mg is produced from the title compound (enantiomer 1) of embodiment 51 and the 14.0mg title compound (enantiomer 2) from embodiment 52 from the stage enantiomer separation of the racemic mixture of embodiment 50 according to method 9D 35.5mg.
LC-MS (method 5B): R t=1.00min; MS (ESIpos): m/z=479 [M+H] +;
HPLC (method 9E): R t=6.78min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.53(d，2H)，7.45(d，2H)，3.96(d，1H)，3.71-3.46(m，5H)，3.42-3.35(m，1H)，3.09-2.84(m，5H)，2.71(d，2H)，2.29(d，1H)，2.16-2.08(m，1H)，2.02-1.90(m，4H)，1.10-1.02(m，2H)，0.93-0.85(m，2H)。
embodiment 53
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of racemization]
React from the compound of embodiment 54A and 63.6mg (0.184mmol) m-chloroperoxybenzoic acid according to general method 2,34.1mg (0.074mmol).Productive rate: 37.1mg (theoretical 99%)
LC-MS (method 5B): R t=1.06min; MS (ESIpos): m/z=495 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.52(d，2H)，7.44(d，2H)，4.00(d，1H)，3.69-3.56(m，5H)，3.41-3.34(m，1H)，3.17(br.s.，4H)，3.10-2.95(m，3H)，2.28(d，1H)，2.17-2.07(m，1H)，2.03-1.89(m，4H)，1.10-1.01(m，2H)，0.94-0.85(m，2H)。
embodiment 54
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidin-1-yl }-(1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
13.0mg is produced from the title compound (enantiomer 1) of embodiment 54 and the 14.0mg title compound (enantiomer 2) from embodiment 55 from the stage enantiomer separation of the racemic mixture of embodiment 53 according to method 9D 37.1mg.
HPLC (method 9E): R t=5.81min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.52(d，2H)，7.44(d，2H)，4.00(d，1H)，3.69-3.56(m，5H)，3.41-3.34(m，1H)，3.17(br.s.，4H)，3.10-2.95(m，3H)，2.28(d，1H)，2.17-2.07(m，1H)，2.03-1.89(m，4H)，1.10-1.01(m，2H)，0.94-0.85(m，2H)。
embodiment 55
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(1,1-bis-fluoro ethyl) phenyl] piperidin-1-yl }-(1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
13.0mg is produced from the title compound (enantiomer 1) of embodiment 54 and the 14.0mg title compound (enantiomer 2) from embodiment 55 from the stage enantiomer separation of the racemic mixture of embodiment 53 according to method 9D 37.1mg.
HPLC (method 9E): R t=9.63min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.52(d，2H)，7.44(d，2H)，4.00(d，1H)，3.69-3.56(m，5H)，3.41-3.34(m，1H)，3.17(br.s.，4H)，3.10-2.95(m，3H)，2.28(d，1H)，2.17-2.07(m，1H)，2.03-1.89(m，4H)，1.10-1.01(m，2H)，0.94-0.85(m，2H)。
embodiment 56
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(difluoro-methoxy) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of racemization]
Start to add in 0.8ml DMF 100mg (0.23mmol) from the compound of embodiment 37A and 46mg (0.46mmol) N-hydroxyl cyclopropane-1-carboximidamide and with 132mg (0.35mmol) HATU and 0.12ml (90mg, 0.69mmol) DIPEA reaction.Reaction mixture stirs 15 minutes and then distributes between water and ethyl acetate under RT.Organic phase repeatedly washes with water, is also under reduced pressure concentrated by dried over sodium sulfate.Resistates absorbs and at 180 DEG C, transform 2 minutes in microwave in 3.0ml DMF.Reaction mixture is purified by preparative HPLC.Productive rate: 46mg (theoretical 37%)
LC-MS (method 2B): R t=1.20min; MS (ESIpos): m/z=497 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.43-7.30(m，2H)，7.14(d，2H)，4.09(q，1H)，3.99(br.d，1H)，3.63(br.d.，1H)，3.40-3.33(m，1H)，3.33-3.28(m，4H)，3.22-3.10(m，4H)，3.08-2.88(m，3H)，2.28(br.d，1H)，2.16-2.07(m，1H)，2.00-1.87(m，1H)，1.12-0.99(m，2H)，0.94-0.84(m，2H)。
embodiment 57
{ 3-[4-(difluoro-methoxy) phenyl]-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of racemization]
Start to add in 2.6m l DMF 300mg (0.69mmol) from the compound of embodiment 37A and 246mg (2.08mmol) N '-hydroxy-3-methoxy third amidine and with 396mg (1.0mmol) HATU and 0.36ml (269mg, 2.1mmol) DIPEA reaction.Reaction mixture stirs 15 minutes and then distributes between water and ethyl acetate under RT.Organic phase repeatedly washes with water, is also under reduced pressure concentrated by dried over sodium sulfate.Resistates absorbs and at 180 DEG C, transform 2 minutes in microwave in 2.0ml DMF.Reaction mixture is purified by preparative HPLC.Productive rate: 141mg (theoretical 38%)
LC-MS (method 2B): R t=1.10min; MS (ESIpos): m/z=515 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.43-7.33(m，2H)，7.15(d，2H)，4.11-3.99(m，2H)，3.71-3.64(m，3H)，3.64-3.55(m，4H)，3.46-3.35(m，1H)，3.35-3.30(m，4H)，3.18(br.s，3H)，3.14-2.90(m，5H)，2.30(br. d，1H)，2.03-1.92(m，1H)。
embodiment 58
{ 3-[4-(difluoro-methoxy) phenyl]-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
43mg is produced from the compound (enantiomer 1) of embodiment 58 and the 38mg compound (enantiomer 2) from embodiment 59 from the stage enantiomer separation of the racemic mixture of embodiment 57 according to method 10D 117mg.
HPLC (method 10E): R t=4.17min, > 99.0%ee;
LC-MS (method 2B): R t=1.10min; MS (ESIpos): m/z=515 [M+H] +.
embodiment 59
{ 3-[4-(difluoro-methoxy) phenyl]-5-[3-(2-methoxy ethyl)-1,2,4- diazole-5-base] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone [cis-isomeride of enantiomer-pure]
43mg is produced from the compound (enantiomer 1) of embodiment 58 and the 38mg compound (enantiomer 2) from embodiment 59 from the stage enantiomer separation of the racemic mixture of embodiment 57 according to method 10D 117mg.
HPLC (method 10E): R t=9.24min, > 99.0%ee;
LC-MS (method 2B): R t=1.10min; MS (ESIpos): m/z=515 [M+H] +.
embodiment 60
{ 3-(3-cyclopropyl-1,2,4- diazole-5-base)-5-[4-(difluoro-methoxy) phenyl] piperidin-1-yl } (1-oxo thiomorpholine-4-base) ketone [cis-isomeride of racemization]
Start to add in 1.8ml DMF 200mg (0.48mmol) from the compound of embodiment 39A and 96mg (0.96mmol) N '-hydroxyl cyclopropane-1-carboximidamide and with 274mg (0.72mmol) HATU and 0.25ml (186mg, 1.44mmol) DIPEA reaction.Reaction mixture stirs 15 minutes and then distributes between water and ethyl acetate under RT.Organic phase repeatedly washes with water, is also under reduced pressure concentrated by dried over sodium sulfate.Resistates is dissolved in 2.0mlDMF and at 180 DEG C, transforms 2 minutes in microwave.Reaction mixture is purified by preparative HPLC.Productive rate: 25mg (theoretical 10%)
LC-MS (method 2B): R t=1.12min; MS (ESIpos): m/z=481 [M+H] +;
1H NMR(400MHz，DMSO-d 6)：δ＝7.42-7.35(m，2H)，7.14(d，2H)，4.01-3.87(m，1H)，3.69-3.45(m，5H)，3.42-3.34(m，1H)，3.07-2.85(m，5H)，2.70(br.d，2H)，2.34-2.23(m，1H)，2.15-2.07(m，1H)，1.99-1.88(m，1H)，1.12-1.01(m，2H)，0.94-0.85(m，2H)。
embodiment 61
(1,1-dioxothiomorpholin-4-base) { 3-[3-(1-mcthoxycyclopropyl)-1,2,4- diazole-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of racemization]
React from the compound of embodiment 65A and 49.0mg (0.142mmol) m-chloroperoxybenzoic acid according to general method 2,29.0mg (0.162mmol).Productive rate: 31.2mg (theoretical 95%)
LC-MS (method 5B): R t=1.06min; MS (ESIpos): m/z=543 [M+H] +;
1H NMR (400MHz，DMSO-d 6)：δ＝7.37-7.29(m，4H)，4.02(d，1H)，3.68-3.55(q，7H)，3.38(s，3H)，3.17(br.s.，4H)，3.10-2.88(m，3H)，2.30(d，1H)，1.95(q，1H)，1.34-1.28(m，2H)，1.20-1.12(m，2H)。
embodiment 62
(1,1-dioxothiomorpholin-4-base) { 3-[3-(1-mcthoxycyclopropyl)-1,2,4- diazole-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
12.0mg is produced from the title compound (enantiomer 1) of embodiment 62 and the 12.0mg title compound (enantiomer 2) from embodiment 63 from the stage enantiomer separation of the racemic mixture of embodiment 61 according to method 11D 31.2mg.
LC-MS (method 2B): R t=1.26min; MS (ESIpos): m/z=543 [M+H] +;
HPLC (method 11E): R t=17.9min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.37-7.29(m，4H)，4.02(d，1H)，3.68-3.55(q，7H)，3.38(s，3H)，3.17(br.s.，4H)，3.10-2.88(m，3H)，2.30(d，1H)，1.95(q，1H)，1.34-1.28(m，2H)，1.20-1.12(m，2H)。
embodiment 63
(1,1-dioxothiomorpholin-4-base) { 3-[3-(1-mcthoxycyclopropyl)-1,2,4- diazole-5-base]-5-[4-(2,2,2-trifluoroethyl) phenyl] piperidin-1-yl } ketone [cis-isomeride of enantiomer-pure]
12.0mg is produced from the title compound (enantiomer 1) of embodiment 62 and the 12.0mg title compound (enantiomer 2) from embodiment 63 from the stage enantiomer separation of the racemic mixture of embodiment 61 according to method 11D 31.2mg.
LC-MS (method 2B): R t=1.26min; MS (ESIpos): m/z=543 [M+H] +;
HPLC (method 11E): R t=29.2min, > 99.0%ee;
1H NMR(400MHz，DMSO-d 6)：δ＝7.37-7.29(m，4H)，4.02(d，1H)，3.68-3.55(q，7H)，3.38(s，3H)，3.17(br.s.，4H)，3.10-2.88(m，3H)，2.30(d，1H)，1.95(q，1H)，1.34-1.28(m，2H)，1.20-1.12(m，2H)。
B) the evaluation of physiologically active
abbreviation:
BSA bovine serum albumin
DMEM Dulbecco improves Eagle substratum
EGTA ethylene glycol-bis-(2-amino-ethyl)-N, N, N ', N '-tetraacethyl
FCS foetal calf serum
HEPES 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid
[3H] haTRAP tritiate high affinity Glycoprotein
PRP platelet rich plasma.
The suitability of the compounds of this invention treatment thromboembolic disorders can show in following test system:
1.) in vitro tests
The function of cell in 1.a) testing in vitro
The antagonist of recombinant cell lines for the identification of human protease activated receptor 1 (PAR-1) and the activity of quantification material described here.The initial derived from human embryonic nephrocyte of this cell (HEK293; ATCC:American Type Culture Collection, Manassas, VA20108, the U.S.).The modified form of calcium sensitive luminescent albumen aequorin is expressed on test clone composition ground, its, after recombinating with cofactor coelenterazine, luminescence (the Rizzuto R when the concentration of the free ca in mitochondrial compartment (compartment) increases, Simpson AW, Brini M, Pozzan T.; Nature 1992,358,325-327).In addition, endogenous people PAR-1 acceptor and endogenous purinergic receptor P2Y2 are expressed in this cytotostatic ground.With the release of intracellular calcium, the PAR-1 produced tests the stimulation of endogenous PAR-1 or the P2Y2 acceptor of cellular response, it can quantize (Milligan G by the suitable photometer of aequorin fluorescence produced, Marshall F, Rees S, Trends in Pharmacological Sciences 1996,17,235-237).
In order to substances specificity, the effectiveness comparison after endogenous PAR-1 receptor activation after its effect and the endogenous purine P2Y2 receptor activation using signalling channel in same cell.
testing sequence:before test, in the microtiter plate of 384-hole, at substratum, (DMEM F12, supplements with 10%FCS, 2mM glutamine, 20mm HEPES, 1.4mM pyruvate salt, 0.1mg/ml gentamicin, 0.15% sodium bicarbonate cell; Bio Whittaker Cat.#BE04-687Q; B-4800Verviers, Belgium) in plate trace two days (48h) at cell culture incubator (96% atmospheric moisture, 5%v/v CO 2, 37 DEG C) and middle preservation.Test the same day, substratum by tyrode's solution (in units of mM: 140 sodium-chlor, 5 Repone K, 1 magnesium chloride, 2 calcium chloride, 20 glucose, 20HEPES) replace, this solution comprises cofactor coelenterazine (25 μMs) and gsh (4mM) in addition, and microtiter plate and then cultivate 3-4 hour.Then substances is pipetted on microtiter plate, and substances transfers to the Kong Zhonghou 5 minutes of microtiter plate, and plate is transferred in photometer, adds corresponding to EC 50pAR-1 agonist enriched material and in photometer, measure the optical signal of generation at once.In order to distinguish antagonist agent effect and toxic action, endogenous purinergic receptor is immediately used agonist (ATP, ultimate density 10 μMs) to activate and is measured the optical signal produced.Result shows in Table A:
table A:
Embodiment number IC 50[nM]
1 43
8 33
10 8.0
15 5.1
20 23
31 32
52 4.7
54 4.3
61 15.7
1.b) PAR-1 receptor binding assays
Platelet membrane 12nM [3H] haTRAP and substances at room temperature cultivate 80min with different concentration in damping fluid (50mM Tris pH7.5,10mM magnesium chloride, 1mM EGTA, 0.1%BSA).Then mixture proceeds to screen plate and with buffer solution twice.After adding scintillation solution, in beta counter, measure radioactivity on the filter.
Platelet aggregation 1.c) in blood plasma
In order to measure platelet aggregation, use the blood of the healthy volunteer from two kinds of sexes, it does not connect the pharmacological agent of the platelet aggregation that is affected for nearest ten days.Blood absorbs and enters monovette (Sarstedt, N ü mbrecht, Germany), and it comprises Trisodium Citrate 3.8% (1 portion of Citrate trianion+9 parts of blood) as antithrombotics.In order to obtain plateletrich blood plasma, citrated whole blood is centrifugal 20min under 140g.
In order to measure cohesion, the plateletrich blood plasma with the substances increasing concentration of decile cultivates 10min at 37 DEG C.Subsequently, by add in aggregometer thrombin receptor agonist (TRAP6, SFLLRN) cause cohesion and according to Born (Born, G.V.R., Cross M.J., The Aggregation of Blood Platelets at 37 DEG C; J.Physiol.1963,168,178-195) measured by tuurbidimetry.Produce the SFLLRN concentration of maximum cohesion, as suitable, each donor is measured respectively.
In order to calculate inhibition, in existence and the maximum increased value (amplitude of cohesion curve is in units of %) measuring light transmission after not having to add agonist when substances in 5 minutes, and calculate suppression.Suppress curve for calculating the concentration suppressing cohesion 50%.Result is presented in table B:
table B:
Embodiment number IC 50[μM]
8 0.29
10 0.49
13 0.17
52 0.58
Platelet aggregation 1.d) in damping fluid
In order to measure platelet aggregation, use the blood of the healthy volunteer from two kinds of sexes, this volunteer does not connect the pharmacological agent of the platelet aggregation that is affected for nearest ten days.Blood absorbs and enters monovette (Sarstedt, N ü mbrecht, Germany), and it comprises Trisodium Citrate 3.8% (1 portion of Citrate trianion+9 parts of blood) as antithrombotics.In order to obtain plateletrich blood plasma, citrated whole blood is centrifugal 20min under 140g.1/4th of ACD damping fluid (44.8mM Trisodium Citrate, 20.9mM citric acid, 74.1mM glucose and 4mM Repone K) volume are added in PRP, and under 1000g centrifugal 10 minutes.Thrombocyte bead lavation buffer solution settling flux under 1000g centrifugal 10 minutes.Thrombocyte is being cultivated settling flux in damping fluid and is adjusting to 200 000 cells/μ l.Before on-test, add calcium chloride and magnesium chloride, at each occurrence ultimate density 2mM (2M stock solution, diluent 1: 1000).Attention: with regard to the cohesion of ADP-induction, only add calcium chloride.Following agonist can be used: TRAP6-trifluoroacetate, collagen protein, people's α-zymoplasm and U-46619.For each donor, the concentration of test agonist.
testing sequence:use 96-hole microtiter plate.Substances is diluted in DMSO, and starts every hole and add 2 μ l.Add 178 μ l platelet suspension, and mixture at room temperature preculture 10 minutes.Add 20 μ l agonists, and get started mensuration in Spectramax, OD405nm.At 1 minute, in 11 mensuration, each measured kinetics.Between mensuration, mixture vibrated for 55 seconds.
1.e) consuming the platelet aggregation in fibrinogenic blood plasma
In order to measure platelet aggregation, use the blood of the healthy volunteer from two kinds of sexes, this volunteer does not connect the pharmacological agent of the platelet aggregation that is affected for nearest ten days.Blood absorbs and enters monovette (Sarstedt, N ü mbrecht, Germany), and it comprises Trisodium Citrate 3.8% (1 portion of Citrate trianion+9 parts of blood) as antithrombotics.
consume the preparation of fibrinogenic blood plasma:in order to obtain low-thrombocyte plasma, citrated whole blood is centrifugal 20min under 140g.Low-thrombocyte plasma with 1: 25 ratio and reptilase (Roche Diagnostic, Germany) mixing and transforming carefully.This cultivates 10min in a water bath succeeded by 37 DEG C, then directly cultivates 10min on ice.Blood plasma/snake poison blood coagulation enzyme mixture centrifugal 15min under 1300g, and obtain supernatant liquor (consuming fibrinogenic blood plasma).
thrombocyte is separated:in order to obtain plateletrich blood plasma, citrated whole blood is centrifugal 20min under 140g.1/4th of ACD damping fluid (44.8mM Trisodium Citrate, 20.9mM citric acid, 74.1mM glucose and 4mM Repone K) volume are added in PRP, and under 1300g centrifugal 10 minutes.Thrombocyte bead lavation buffer solution settling flux under 1300g centrifugal 10 minutes.Thrombocyte is being cultivated settling flux in damping fluid and is adjusting to 400000 cells/μ l, and adds the calcium chloride solution with ultimate density 5mM (1/200 dilution).
In order to measure cohesion, the aliquots containig (98 μ l consume fibrinogenic blood plasma and 80 μ l platelet suspension) with the substances increasing concentration cultivates 10min under RT.Subsequently, by add in aggregometer people α zymoplasm cause cohesion and according to Born (Born, G.V.R., Cross M.J., The Aggregation of Blood Platelets at 37 DEG C; J.Physiol.1963,168,178-195) measured by tuurbidimetry.Each donor is measured respectively to the α concentration of thrombin just producing maximum condensation number.
In order to calculate inhibition, in existence with after there is no to add agonist when substances, in 5 minutes, measuring the increased value of maximum transmission (amplitude of cohesion curve is in units of %), and calculate suppression.Suppress curve for calculating the concentration suppressing cohesion 50%.
1.f) the hematoblastic stimulation of washing and the analysis in flow cytometry
the hematoblastic separation of washing:people's whole blood to be obtained by venipuncture and the monovette (Sarstedt, N ü mbrecht, Germany) proceeding to the Trisodium Citrate (1 part of Trisodium Citrate 3.8%+9 part whole blood) comprised as antithrombotics by volunteering donor.Monovette is centrifugal 20 minutes (Heraeus Instruments, Germany at per minute 900 turns and 4 DEG C; Megafuge 1.0RS).The plateletrich blood plasma of careful removing also proceeds to 50ml Falcon test tube.Then in this blood plasma, add ACD damping fluid (44mM Trisodium Citrate, 20.9mM citric acid, 74.1mM glucose).The volume of ACD damping fluid corresponds to 1/4th of Plasma volumes.Centrifugal ten minutes pellet platelets at 2500rpm and 4 DEG C.After this, decant falls supernatant liquor and abandons carefully.The thrombocyte of precipitation is first carefully at one milliliter of lavation buffer solution (113mM sodium-chlor, 4mM Sodium phosphate dibasic, 24mM SODIUM PHOSPHATE, MONOBASIC, 4mM Repone K, 0.2mM ethylene glycol-bis-(2-amino-ethyl)-N, N, N ' N '-tetraacethyl, 0.1% glucose) in settling flux and then supplementary lavation buffer solution to the volume of the volume of the amount with corresponding blood plasma.Repeated washing step.By centrifugal ten minutes pellet platelets and then cultivate damping fluid (134mM Sodium chloride deposit at a milliliter carefully again at 2500rpm and 4 DEG C, 12mM sodium bicarbonate, 2.9mM Repone K, 0.34mM SODIUM PHOSPHATE, MONOBASIC, 5mM HEPES, 5mM glucose, 2mM calcium chloride and 2mM magnesium chloride) in settling flux adjust to the hematoblastic concentration of every μ l 300000 with cultivation damping fluid.
when there is or do not have PAR-1 antagonist, employment α-zymoplasm dyes and swashs human blood platelets:platelet suspension is preculture 10 minutes (Eppendorf, Germany at 37 DEG C with the material that will test or suitable solvent; Thermomixer Comfort).At 37 DEG C and with vibrating by adding agonist (0.5 μM or 1 μM of α-zymoplasm at 500 rpm; Kordia, Holland, 3281NIH unit/mg; Or 30 μ g/ml Glycoproteins (TRAP6); Bachem, Switzerland) cause platelet activation.One 50 μ l aliquots containigs removed in often kind of situation at 0,1,2.5,5,10 and 15 minute, and transfer enters one milliliter of CellFix concentrated separately tMsolution (Becton Dickinson Immunocytometry Systems, the U.S.).In order to fixed cell, they cultivate 30 minutes in the dark at 4 DEG C.By centrifugal ten minutes pellet platelets at 600g and 4 DEG C.Abandon supernatant liquor and thrombocyte at 400 μ l CellWash tMsettling flux in (Becton Dickinson Immunocytometry Systems, the U.S.).One 100 μ l aliquots containigs proceed to new FACS test tube.Use Cell Wash tM1 μ l thrombocyte-qualification antibody and 1 μ l state of activation-detection antibody supplement are to 100 μ l volumes.Then in platelet suspension, add this antibody-solutions and cultivate 20 minutes at 4 DEG C in the dark.After dyeing, this reaction volume is by adding 400 μ lCellWash further tMincrease.
Human glucoprotein IIb (CD41) (Immunotech Coulter, France; Goods catalogue numbering 0649) the antibody of fluorescein isothiocyanate-conjugation for differentiating thrombocyte.Human glucoprotein palatelet-selectin (Immunotech Coulter, France is aimed at by means of direction; Goods catalogue numbering 1759) the antibody of phycoerythrobilin-conjugation, hematoblastic state of activation can be measured.Palatelet-selectin (CD62P) is located in the hematoblastic α-particle stopped.But along with external or body internal stimulus, it crosses over location (translocalized) to external plasma film.
flow cytometry and data evaluation:sample is at the FAC SCal ibur from Becton Dickinson Immunocytometry Systems, USA tManalyze in Flow Cytometry System instrument, and evaluate and by CellQuest software, version 3 .3 (Becton Dickinson Immunocytometry Systems, the U.S.) diagram presents.The degree of platelet activation is measured by the percentage of CD62P-positive blood platelet (CD41-positive events).By each sample, calculate the situation of 10000 CD41-positives.
The inhibition of the material tested is calculated by the minimizing in platelet activation, and it relates to the activation by agonist.
Parallel flat flow chamber 1.g) is used to measure platelet aggregation
Use the hematometry platelet activation from the healthy volunteer of two kinds of sexes, this volunteer does not connect the pharmacological agent of the platelet aggregation that is affected for nearest ten days.Blood absorbs and enters monovette (Sarstedt, N ü mbrecht, Germany), and it comprises Trisodium Citrate 3.8% (1 portion of Citrate trianion+9 parts of blood) as antithrombotics.In order to obtain plateletrich blood plasma, citrated whole blood is centrifugal 20min under 140g.The ACD damping fluid (44.8mM Trisodium Citrate, 20.9mM citric acid, 74.1mM glucose and 4mM Repone K) of 1/4th volumes is added in PRP, and mixture under 1000g centrifugal 10 minutes.Thrombocyte bead settling flux in lavation buffer solution and under 1000g centrifugal 10 minutes.In order to perfusion studies, prepare the mixture of 40% red blood corpuscle and 60% washing platelet (200000/ μ l) and be suspended in HEPES-Di Luode damping fluid.Parallel flat flow chamber is used to measure platelet aggregation (B.Nieswandt etc., EMBO J.2001,20,2120-2130 under the flow conditions; C.Weeterings, Arterioscler Thromb.Vasc.Biol.2006,26,670-675; JJ Sixma, Thromb.Res.1998,92,43-46).At 4 DEG C, the slide glass solution-wet of 100 μ l people α-zymoplasms (being dissolved in Tris damping fluid) is spent the night (α-zymoplasm with different concentration, such as 10 to 50 μ g/ml) and is then used 2%BSA to close.
The blood reconstituted under constant flow rate (such as the shearing rate in 300/ second) by zymoplasm-wetting slide glass 5 minutes and use microscope video system observe and record.The inhibit activities of the material tested is measured by the minimizing form of thrombocyte formation of the agglomerates effect.Or the suppression of platelet activation can pass through flow cytometry, such as, select element to express (CD62p) (see method 1.f) by p-and measure.
1.h) use parallel flat flow chamber (anticoagulation, collagen protein) to measure platelet aggregation and activation
Use the blood from the healthy volunteer of two kinds of sexes to measure platelet activation under the flow conditions, this volunteer does not connect the pharmacological agent of the platelet aggregation that is affected for nearest ten days.Blood absorbs and enters monovette (Sarstedt, N ü mbrecht, Germany).It comprises Trisodium Citrate 3.8% (1 portion of Citrate trianion+9 parts of blood) as antithrombotics.
Parallel flat flow chamber is used to carry out mensuration (B.Nieswandt etc., EMBO J.2001,20, the 2120-2130 of platelet activation; C.Weeterings, Arterioscler Thromb.Vasc.Biol.2006,26,670-675; JJ Sixma, Thromb.Res.1998,92,43-46).At 4 DEG C, slide glass spends the night (such as, with the type i collagen protein of different concentration, 1-10 μ g/ slide glass) with 20 μ l collagen suspension liquid (collagen protein reagent: Horm, Nycomed) are wetting and finally use 2%BSA to close.
Condense to prevent scleroproein and formed, whole blood and Pefabloc FG (Pentapharm, ultimate density 3mM) containing Citrate trianion mix, and, by interpolation CaCl 2solution (last Ca ++concentration 5mM), under constant flow rate, pass through the slide glass (such as the shearing rate of 1000/ second) 5 minutes of collagen protein-coating and use microscope video system to observe and record.The inhibition of the material tested is measured by the minimizing form of thrombocyte formation of the agglomerates effect.Or the suppression of platelet activation can pass through flow cytometry, such as, select element to express (CD62p) (see method 1.f) by p-and measure.
Parallel flat flow chamber (non-anticoagulation, collagen protein) 1.i) is used to measure platelet aggregation and activation
Use the blood from the healthy volunteer of two kinds of sexes to measure platelet activation under the flow conditions, this volunteer does not connect the pharmacological agent of the platelet aggregation that is affected for nearest ten days.Blood absorbs neutral monovette (Sarstedt, N ü mbrecht, Germany) in, it does not comprise any antithrombotics, and mix with Pefabloc FG (Pentapharm, ultimate density 3mM) at once and formed to prevent scleroproein from condensing.Add with Pefablock FG the substances being dissolved in DMSO further not cultivate and join in parallel flat flow chamber simultaneously.The mensuration of platelet activation is carried out in the parallel plate flow chambers of collagen protein-coating by morphometry or flow cytometry, as at method 1.h) in describe.
2.) in vitro tests
2.a) platelet aggregation (primate, cavy)
Clear-headed or the cavy of anesthesia or primate by substances with suitable preparation per os, intravenously or intraperitoneal therapy.In contrast, other cavy or primate are treated with corresponding vehicle in an identical manner.Depend on the mode taken, the blood of the animal of deep anaesthesia is obtained by the puncture heart of different time periods or aorta.Blood absorbs in monovette (Sarstedt, N ü mbrecht, Germany), and it comprises Trisodium Citrate 3.8% (1 part of citrate solution+9 parts of blood) as antithrombotics.In order to obtain plateletrich blood plasma, citrated whole blood is centrifugal 20min under 140g.
In aggregometer, cohesion (TRAP6, SFLLRN, 50 μ g/ml are caused by adding thrombin receptor agonist; In each experiment, concentration is measured to each animal species) and (Born, G.V.R., Cross M.J., The Aggregation of Blood Platelets is measured by tuurbidimetry according to Born at 37 DEG C; J.Physiol.1963,168,178-195).
In order to measure cohesion, in 5 minutes, after adding agonist, measure the maximum increased value (amplitude of the cohesion curve in units of %) of light transmission.The inhibition of the substances taken in treatment animal is calculated, based on this mean value of control animal by the minimizing of cohesion.
Except measuring cohesion, the suppression of platelet activation can pass through flow cytometry, such as, select element to express (CD62p) (see method 1.f) by p-and measure.
2.b) in parallel flat flow chamber, measure platelet aggregation and activation (primate)
Primate that is clear-headed or anesthesia by substances with suitable preparation per os, intravenously or intraperitoneal therapy.In contrast, other animal is treated with corresponding vehicle in an identical manner.Depend on the mode taken, blood was obtained from this animal by venipuncture by the different time periods.Blood is transferred in monovette (Sarstedt, N ü mbrecht, Germany), and it comprises Trisodium Citrate 3.8% (1 part of citrate solution+9 parts of blood) as antithrombotics.Or non-anticoagulation can gather with neutral monovettes (Sarstedt).In both cases, blood and Pefabloc FG (Pentapharm, ultimate density 3mm) mix and are formed to prevent scleroproein from condensing.
Containing before the whole blood assay of Citrate trianion by adding CaCl 2solution (last Ca++ concentration 5mM) calcification again (recalcify).Directly join in parallel flat flow chamber to measure non-anticoagulation.The mensuration of platelet activation is carried out in the parallel flat flow chamber of collagen protein-coating by morphometry or flow cytometry, as at method 1.h) in describe.
3.) in vivo test
3.a) thrombotic model
The compounds of this invention can be studied in thrombotic model in suitable animal species, and the platelet aggregation of wherein zymoplasm-induction is by PAR-1 regulation.Suitable animal species be cavy and, particularly, primate is (referring to Lindahl, A.K., Scarborough, R.M., Naughton, M.A., Harker, L.A., Hanson, S.R., Thromb Haemost1993,69,1196; Cook JJ, Sitko GR, Bednar B, Condra C, Mellott MJ, Feng D-M, Nutt RF, Shager JA, Gould RJ, Connolly TM, Cirrculation1995,91,2961-2971; Kogushi M, Kobayashi H, Matsuoka T, Suzuki S, Kawahara T, Kajiwara A, Hishinuma I, Circulation2003,108Suppl.17, IV-280; Derian CK, Damiano BP, Addo MF, Darrow AL, D ' Andrea MR, Nedelman M, Zhang H-C, Maryanoff BE, Andrade-Gordon P, J.Pharmacol.Exp.Ther.2003,304,855-861).Or, can use and use the pretreated cavy of the inhibitor of PAR-3 and/or PAR-4 (Leger AJ etc., Circulation2006,113,1244-1254), or the cavy that genetically modified PAR-3-and/or PAR-4-knocks down.
3.b) damaging blood coagulation and organ dysfunction in disseminated inravascular coagulation situation (DIC)
The compounds of this invention can be tested in the model of DIC and/or septicemia in suitable animal species.Suitable animal species is cavy and particularly primate, with the effect in order to study endothelium-adjustment and Mouse and rat (referring to Kogushi M, Kobayashi H, Matsuoka T, Suzuki S, Kawahara T, Kajiwara A, Hishinuma I, Circulation 2003,108Suppl.17, IV-280; Derian CK, Damiano BP, Addo MF, Darrow AL, D ' Andrea MR, Nedelman M, Zhang H-C, Maryanoff BE, Andrade-Gordon P, J.Pharmacol.Exp.Ther.2003,304,855-861; Kaneider NC etc., Nat Immunol, 2007,8,1303-12; Camerer E etc., Blood, 2006,107,3912-21; Riewald M etc., J Biol Chem, 2005,280,19808-14).Or, can use and use the pretreated cavy of the inhibitor of PAR-3 and/or PAR-4 (Leger AJ etc., Circulation 2006,113,1244-1254), or the cavy that genetically modified PAR-3-and/or PAR-4-knocks down.
3.b.1) thrombin-antithrombin complex title complex
Thrombin-antithrombin complex title complex (hereinafter referred to as " TAT ") is the yardstick being formed zymoplasm by Activated Coagulation endogenous.TAT is by ELISA test determination (Enzygnost TAT micro, Dade-Behring).Blood plasma by citrated blood by centrifugal acquisition.In 50 μ l blood plasma, add 50 μ l TAT sample buffers, brief vibration also at room temperature cultivates 15min.Sample suction filtration, and hole lavation buffer solution (300 μ L/ hole) washs 3 times.Between washing step, pat plate to remove the lavation buffer solution of any remnants.Add conjugate solutions (100 μ L) and mixture at room temperature cultivates 15min.Sample suction filtration, and hole lavation buffer solution (300 μ L/ hole) washs 3 times.Then add chromogenic substrate (100 μ L/ hole), mixture at room temperature cultivates 30min in the dark, adds stop bath (100 μ L/ hole), and under 492nm, measures the development (Safire plate reader) of color.
3.b.2) the parameter of organ dysfunction
Measure various parameter, the restriction of its function considered owing to taking the various internal organ of LPS makes it possible to reach a conclusion, and can estimate the result for the treatment of of substances.Centrifugal citrated blood or, as suitable, lithium heparinemia, and blood plasma be used for location parameter.Usually, measure following parameter: creatinine, urea, aspartate amino transferase (AST), alanine aminotransferase (ALT), total bilirubin, serum lactic dehydrogenase (LDH), total protein, total albumin and Fibrinogen.This value provides and renal function, liver function, the information that cardiovascular function is relevant with vascular function.
3.b.3) the parameter of inflammation
The degree of the inflammatory reaction caused by intracellular toxin can such as, by inflammatory mediator, interleukin (1,6,8 and 10) in blood plasma, the rising display of tumor necrosis factor alpha or monocyte chemoattractant protein-1.ELISA or Luminex system may be used for this object.
3.c) anti-tumor activity
The compounds of this invention can in the model of cancer, such as test in the mouse of immunological incompetence in human breast carcinoma model (referring to: S.Even-Ram etc., Nature Medicine, 1988,4,909-914).
3.d) anti-angiogenesis activity
The compounds of this invention can be tested in the in vitro and in vivo model of vasculogenesis (referring to: Caunt etc., Journal of Thrombosis and Haemostasis, 2003,10,2097-2102; Haralabopoulos etc., Am J Physiol, 1997, C239-C245; Tsopanoglou etc., JBC, 1999,274,23969-23976; Zania etc., JPET, 2006,318,246-254).
The activity of 3.e) blood pressure-and pulse-adjustment
The compounds of this invention can test their impacts for arteriotony and heart rate in vivo in model.For this purpose, rat (such as Wei Sita) wears implanted wireless telemetering system, and use the electronic data acquisition and storage system (Data Sciences, MN, the U.S.) that are made up of the long-term implantable sensor/launching device of the conduit in conjunction with filling liquid.Peritoneal cavity implanted by projector, and sensor conduit is located in descending aorta.The compounds of this invention can be taken (such as per os or intravenously).Before treatment, measure mean arterial blood pressure and the heart rate of animal that is untreated and that treat, and ensure that they clap/minute scope at about 131-142mmHg and 279-321.Intravenously takes PAR-1-activated peptide (SFLLRN; Such as dosage is at 0.1-5mg/kg).There iing and do not having PAR-1-activated peptide and having and measure blood pressure and heart rate under there is no a kind of the compounds of this invention situation (referring to Cicala C etc., The FASEB Journal, 2001,15,1433-5 under the various timed interval and time length; Stasch JP etc., British Journal of Pharmacology 2002,135,344-355).
3.f) thrombotic model
The thrombus in vivo being suitable for the effect measuring compound of the present invention further forms test at Tucker EI, Marzec UM, White TC, Hurst S, Rugonyi S, McCarty OJT, Gailani D, Gruber A, Hanson SR:Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI.Blood 2009, describe in 113,936-944.
4.) deliquescent mensuration
the preparation of starting soln (original solution):
At least 1.5mg substances by accurate weighing to being furnished with the wide-mouth 10mm spiral V-bottle of nut and barrier film (from Glastechnik gmbH, Item Number 8004-WM-H/V15 μ) in, DMSO is added to the concentration of 50mg/ml and bottle rotates 30 minutes.
the preparation of calibration solution:
The required robot of liquid step by means of operating liquid in 1.2ml 96-hole depth orifice plate (DWP) that move carries out.The solvent used is the mixture of acetonitrile/water 8: 2.
The preparation of the starting soln of calibration solution (stock solution): add 833 μ l solvent mixtures in 10 μ l original solutions (concentration=600 μ g/ml), and mixture homogenization.1: 100 diluent is prepared by each substances in the DWP separated, and these homogenizing successively.
Calibration solution 5 (600ng/ml): add 270 μ l solvent mixtures in 30 μ l stock solutions, and mixture homogenization.
Calibration solution 4 (60ng/ml): calibrate in solution 5 to 30 μ l and add 270 μ l solvent mixtures, and mixture homogenization.
Calibration solution 3 (12ng/ml): calibrate in solution 4 to 100 μ l and add 400 μ l solvent mixtures, and mixture homogenization.
Calibration solution 2 (1.2ng/ml): calibrate in solution 3 to 30 μ l and add 270 μ l solvent mixtures, and mixture homogenization.
Calibration solution 1 (0.6ng/ml): calibrate in solution 2 to 150 μ l and add 150 μ l solvent mixtures, and mixture homogenization.
the preparation of sample solution:
The required robot of liquid step by means of operating liquid in 1.2ml 96-hole DWP that move carries out.1000 μ l PBS pH of buffer 6.5 are added in 10.1 μ l stock solutions.(PBS pH of buffer 6.5:61.86g sodium-chlor, 39.54g SODIUM PHOSPHATE, MONOBASIC and 83.35g 1N sodium hydroxide solution weigh and enter 1 liter of standard jar and add to mark with water, and mixture stirs about 1 hour.In 5 liters of standard jars, add this solution of 500ml and add to mark with water.1N sodium hydroxide solution pH is used to adjust to 6.5)
step:
The required robot of liquid step by means of operating liquid in 1.2ml 96-hole DWP that move carries out.The sample solution prepared by this way is under 1400rpm and use temperature is variable at 20 DEG C oscillator vibrates 24 hours.Gathered 180 μ l by each these solution and shifted and enter Beckman Polyallomer centrifuge tube.These solution centrifugal 1 hour at about 223000 × g.By each sample solution, remove 100 μ l supernatant liquors and dilute with 1: 10 and 1: 1000 with PBS damping fluid 6.5.
analyze:
Sample is analyzed by HPLC/MS-MS.Test compound is quantized by 5 working curves.Solvability mg/l represents.Analysis sequence: 1) blank (solvent mixture); 2) solution 0.6ng/ml is calibrated; 3) solution 1.2ng/ml is calibrated; 4) solution 12ng/ml is calibrated; 5) solution 60ng/ml is calibrated; 6) solution 600ng/ml is calibrated; 7) blank (solvent mixture); 8) sample solution 1: 1000; 9) sample solution 1: 10.
hPLC/MS-MS method:
HPLC:Agilent 1100, pump of constant delivery type (G1311A), self-actuated sampler CTC HTS PAL, de-gassing vessel (G1322A) and post thermostat container (G1316A); Post: Oasis HLB20mm × 2.1mm, 25 μ; Temperature: 40 DEG C; Elutriant A: water+0.5ml formic acid/L; Elutriant B: acetonitrile+0.5ml formic acid/L; Flow velocity: 2.5ml/min; Stand-by time 1.5min; Gradient: 0min 95%A, 5%B; The gradient: 0-0.5min 5%A, 95%B; 0.5-0.84min5%A, 95%B; The gradient: 0.84-0.85min 95%A, 5%B; 0.85-1.5min 95%A, 5%B.MS/MS:WATERS Quattro Micro Tandem MS/MS; Z-Spray API interface; HPLC-MS import separator 1: 20; Measure with ESI pattern.
5.) external clearance rate is measured with liver cell
At 37 DEG C, in 1.5ml cumulative volume, use is improved robot (Perkin Elmer) carries out fresh Primary Hepatocyte Culture, vibrates simultaneously.This cultivation generally comprises 100 ten thousand live body liver cell/ml, about 1 μM of substrate and 0.05M potassium phosphate buffer (pH=7.4).Acetonitrile concentration final in this cultivation is≤1%.
2,10,20,30,50,70 and 90min after by this cultivation take out 125 μ l aliquots containigs and transfer enter 96-hole filter plate (the hydrophilic PTFE of 0.45 μm of weak coupling; Millipore:MultiScreen Solvinert).Each in these comprises 250 μ l acetonitriles to stop this reaction.After centrifugation, filtrate analyzes (usual API3000) with MS/MS.
Use following formula, calculate external clearance rate by the transformation period of material decomposition:
CL ' intrinsic[ml/ (minkg)]=(0.693/ external t1/2 [min]) (liver weight [g liver/kg body weight]) (cell count [1.110^8]/liver weight [g])/(cell count [110^6]/volume of culture [ml])
By following formulae discovery CL bloodand do not consider the fraction (" model that untethered stirs very well ") of dissociating:
CL blood[1/ (hkg)]=(Q of fine stirring h[1/ (hkg)] CL ' intrinsic[1/ (hkg)])/(Q h[1/ (hkg)]+CL ' intrinsic[1/ (hkg)])
Species specific outer push factor for this calculating gathers in the following table;
Male/female Male mouse Female mouse Hero/female mouse Hero/bitch Female dog Male/female people
Cell count/g liver [10 6Cell] 110 110 110 110 110 110
Liver [g]/kg body weight 50 43 32 39 30 21
Hepatic blood flow [l/ (hkg)] 5.4 5.4 4.2 2.1 2.5 1.3
Show the Fmax value of the bioavailability of maximum possible-extract based on liver-be calculated as follows:
F max[%]=(1-(CL of fine stirring blood[1/ (hkg)]/Q of fine stirring h[1/ (hkg)])) 100.
6.) the mensuration of vivo pharmacokinetic
In order to measure interior medicine dynamics, substances be dissolved in different formulation media (such as blood plasma, ethanol, DMSO, PEG400, etc.) or the mixture of these solubilizing agent, and give mouse, rat, dog or monkey intravenously or oral administration are used.As bole or carry out intravenously as injecting and take.Taking dose is from 0.1 to 5mg/kg scope.Blood sample in different periods through 26h at the most by conduit or as sacrificing sampled plasma.In addition, also obtain some organs, tissue and urine samples.This material of calibration sample quantitative assay in the sample by being formed in special matrix.By removing with acetonitrile or methanol extraction the albumen existed in the sample to which.Subsequently, sample by HPLC 2300HTLC system (Cohesive Technologies, Franklin, MA, the U.S.) or Agilent 1200 ( , Germany) and the trans-phase post separation of upper use.HPLC system sprays coupling by the turbine ion being connected to API 3000 or 4000 triple quadrupole mass spectrograph (Applied Biosystems, Darmstadt, Germany).The kinetic assay program appraisal plasma concentration that use confirms the validity is relative to the curve of time.
C) the operation embodiment of pharmaceutical composition
Material of the present invention can be converted into following pharmaceutical preparation:
tablet:
composition:
The compound of 100mg embodiment 1,50mg lactose (mono-hydrate), 50mg W-Gum, 10mg polyvinylpyrrolidone (PVP 25) (from BASF, Germany) and 2mg Magnesium Stearate.
Tablet weight 212mg, diameter 8mm, radius-of-curvature 12mm.
produce:
The compound of embodiment 1,5% strength solution (m/m) granulation of mixture PVP in water of newborn sugar and starch.Particle drying and mix 5 minutes with Magnesium Stearate.Mixture is with conventional tablet presses compression (for the form of tablet see above).
oral suspension:
composition:
The compound of 1000mg embodiment 1,1000mg ethanol (96%), 400mg Rhodigel (xanthan gum) (from FMC, the U.S.) and 99g water.
The single dose of 100mg compound of the present invention is equivalent to 10ml oral suspension.
produce:
Rhodigel suspends in ethanol, and in suspension, add the compound of embodiment 1.Add water to stir simultaneously.Mixture stirs about 6h until Rhodigel terminates to expand.
can the solution taken of intravenously:
composition:
The compound of 1mg embodiment 1,15g poly(oxyethylene glycol) 400 and the water of 250g for injecting.
produce:
The compound of embodiment 1 passes through stirring and dissolving in water together with poly(oxyethylene glycol) 400.Solution sterile filters (pore diameter 0.22 μm) and aseptically preparation enters thermally-sterilized infusion bottle.The latter's infusion plug and pulling cover sealing.

Claims (15)

1. following formula: compound
Wherein
R 1trifluoromethyl, trifluoromethoxy or ethyl,
R 22-hydroxyl second-1-base, 2-methoxyl group second-1-base, 2-oxyethyl group second-1-base or cyclopropyl,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
Or its salt a kind of.
2. formula according to claim 1 (I) compound, is characterised in that
R 1trifluoromethyl or ethyl,
R 22-hydroxyl second-1-base, 2-methoxyl group second-1-base or cyclopropyl,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
Or its salt a kind of.
3. compound according to claim 1, is characterised in that
R 1trifluoromethyl or ethyl,
R 22-methoxyl group second-1-base,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
Or its salt a kind of.
4. compound according to claim 1, wherein phenyl substituent and 1,2,4-oxadiazole-5-base substituting group, it is connected to piperidine ring, at cis-position each other.
5. compound according to claim 1, is characterised in that
R 1trifluoromethoxy,
R 2cyclopropyl,
R 3it is the group of following formula
Wherein
* be the point of contact with carbonyl group,
With their salt.
6. compound according to claim 1, it has following formula:
The cis-isomeride of enantiomer-pure of { 3-(3-cyclopropyl-1,2,4-oxadiazole-5-base)-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone, or its salt.
7. compound according to claim 1, it has following formula:
The cis-isomeride of enantiomer-pure of { 3-(3-cyclopropyl-1,2,4-oxadiazole-5-base)-5-[4-(trifluoromethoxy) phenyl] piperidin-1-yl } (1,1-dioxothiomorpholin-4-base) ketone.
8. prepare formula according to claim 1 (I) compound or its method of salt a kind of, be characterised in that
[A] following formula: compound
Wherein
R 1and R 2each is as defined in claim 1
React with following formula: compound
Wherein
R 3as defined in claim 1, and
X 1halogen, or hydroxyl,
Or
[B] formula (II) compound reacts with chloroformic acid 4-nitre phenyl ester and reacts with following formula: compound in subordinate phase in the first phase
R 3-H(IV)，
Wherein
R 3as defined in claim 1,
Or
[C] following formula: compound
Wherein
R 1and R 3each is as defined in claim 1,
React with following formula: compound
Wherein
R 2as defined in claim 1.
9. method according to claim 8, wherein X 1bromine or chlorine.
10. according to the compound of any one of claim 1 to 7 for the production of the application of medicine treating and/or preventing disease.
11. according to the compound of any one of claim 1 to 7 for the production of the disease and the inflammatory diseases that treat and/or prevent atherosclerotic's blood vessel, the application of the medicine of thromboembolic disorders and/or tumor disease.
The compound of any one of 12. claims 1 to 7 is for the production of the application of the medicine preventing extracorporeal blood from solidifying.
13. comprise the medicine with inertia, nontoxic, that the acceptable vehicle of medicine the is combined compound of any one according to claim 1-7.
14. medicines comprising the compound of any one according to claim 1-7 be combined with further activeconstituents.
15. according to the medicine of claim 13 or 14 for the production of the disease and the inflammatory diseases that treat and/or prevent atherosclerotic's blood vessel, the application of the composition of thromboembolic disorders and/or tumor disease.
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AU2010252339B2 (en) 2014-10-23
DE102009022894A1 (en) 2010-12-02
TWI464166B (en) 2014-12-11
US8202862B2 (en) 2012-06-19
CA2763386A1 (en) 2010-12-02
SG175759A1 (en) 2011-12-29

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